Pyrimidine derivatives having antitumor effect

ABSTRACT

A compound represented by the formula (I):  
                 
 
     wherein, for example, R 1 , R 2 , R 3 , and R 4  are each independently hydrogen atom, alkyl, and the like, R 5  and R 6  are each independently hydrogen atom, alkyl, and the like, R B  and R C  are each independently hydrogen atom, alkyl, and the like, X is —O—, —S—, and the like, Y is 5-membered heteroaryl-diyl and the like, Z is optionally substituted aryl and the like, their pharmaceutically acceptable salts, or their solvates.

TECHNICAL FIELD

[0001] The present invention relates to a novel pyrimidine derivative having an antitumor activity, a cytostatic activity, and an inhibitory activity against a signal derived from Ras oncogene products.

BACKGROUND ART

[0002] The oncogene “ras” such as H-ras, K-ras, and N-ras is mutated and activated in many of neoplasms. The “Ras”, the products of ras oncogene, strongly concerns tumorigenesis caused by acceleration of cell cycle and induction of expression of many of genes associated with a malignant conversion such as a vascular endothelial growth factor and type-IV collagenase. Especially, it is found that there is highly frequent ras mutation in solid tumor such as pancreatic cancer (>80%), colon cancer (>40%), and lung cancer (>20%) which are difficult to be cured by using existing chemotherapeutics. Therefore, it is considered that Ras is one of the most important target molecules in the development of the chemotherapeutics against them.

[0003] A farnesyl-protein-transferase (FPT) inhibitor (FPTI) is known as chemotherapeutics of which target are Ras (WO95/13059, WO95/25086, WO95/25092, WO95/34535, U.S. Pat. No. 5,608,067, and JP-A-7-112930).

[0004] In the cells expressing activated Ras, the excess signals reach cell nucleus through some signaling pathways and some signal transmitter molecules such as MAPK (Mitogen Activated Protein Kinase) and PI3K (Phosphatidylinositol-3-Kinase). The signals activate the transcription factors such as AP1 (Activator Protein-1) and ETS (E26 transformation specific) in the cell nucleus and then they induce the expression of many genes related to malignant features through transcription activation element such as Ras Responsive Element (RRE). Therefore, it is possible to repress the malignant conversion of the cancer cells, when the signal transmission (a signal derived from ras oncogene products) is inhibited. Inhibitors of a signal derived from Ras oncogene products, of which basic structure is similar to that of the compounds of the present invention, are described in WO00/04014.

DISCLOSURE OF INVENTION

[0005] In the above situation, the inventors of the present invention have studied on the antitumor agent having an inhibitory activity against a signal derived from Ras oncogene products.

[0006] The activation of gene expression through RRE is in proportion to a signal derived from Ras and the signal can be measured by the amount of its expression. The inventors of the present invention artificially made cells having activated Ras wherein expression of firefly luciferase gene, reporter gene, is regulated by RRE and carried out a screening of the inhibitors taking luciferase activity shown by the cells as an index of signals through Ras. As a result, the inventors of the present invention found that a series of pyrimidine derivatives have a strong inhibitory activity against a signal derived from Ras oncogene products.

[0007] The present invention relates to I) a compound represented by the formula (I):

[0008] wherein R¹, R², R³, and R⁴ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, an optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or

[0009] R¹and R², R³ and R⁴, and R² and R³ each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered ring optionally containing O, N, or S, provided that R¹and R², and R³ and R⁴ do not form a ring when R² and R³ taken together form a ring;

[0010] R⁵ and R⁶ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro;

[0011] R^(B) and R^(C) are each independently hydrogen atom, alkyl, or alkyloxy; provided that in the case of both of R^(B) and R^(C) are hydrogen atom, R¹ is hydrogen atom or alkyl, R² is optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R³ and R⁴ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or R³ and R⁴ each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered ring optionally containing O, N, or S;

[0012] X is —N(R⁷)—, —NH—NH—, —O—, or —S— wherein R⁷ is hydrogen atom or optionally substituted alkyl;

[0013] Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl;

[0014] Z is optionally substituted aryl or optionally substituted heteroaryl; its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.

[0015] In more detail, the present invention relates to II)-XVI):

[0016] II) a compound described in I), represented by the formula (II)

[0017] wherein R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, a non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro;

[0018] R^(B) and R^(C) are each independently hydrogen atom, alkyl, or alkyloxy; provided that in the case of both of R^(B) and R^(C) are hydrogen atom, R⁸ is hydrogen atom or alkyl, R⁹ is substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R¹⁰ and R¹¹ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro;

[0019] W is —O—, —S—, or —N(R^(A))— wherein R^(A) is hydrogen atom or optionally substituted alkyl;

[0020] R⁵, R⁶, X, and Z are as defined above mentioned I);

[0021] its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.

[0022] III) a compound described in I), represented by the formula (III):

[0023] wherein R⁵, R⁶, and Z are as defined above mentioned I); R⁸, R⁹, R¹⁰, R¹¹, R^(B) and R^(C) are as defined above mentioned II);

[0024] its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.

[0025] IV) a compound described in I), represented by the formula (IV):

[0026] wherein R⁸, R⁹, R¹⁰ and R¹¹ are as defined above mentioned II);

[0027] R¹² is hydrogen atom or alkyl;

[0028] R^(D) and R^(E) are each independently hydrogen atom or alkyl; provided that in the case of both of R^(D) and R^(E) are hydrogen atom, R⁸ is hydrogen atom or alkyl, R⁹ is optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R¹⁰ and R¹¹ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro;

[0029] V is optionally substituted aryl;

[0030] its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.

[0031] V) a compound represented by the formula (V):

[0032] wherein R⁵ and R⁶ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen atoms, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro;

[0033] R^(F) and R^(G) are each independently hydrogen atom, alkyl, or alkyloxy;

[0034] X is —N(R⁷)—, —NH—NH—, —O—, or —S— wherein R⁷ is hydrogen atom or optionally substituted alkyl;

[0035] Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl;

[0036] Z is optionally substituted aryl or optionally substituted heteroaryl;

[0037] Q¹ is —NR¹R², —OR¹, or —SR¹, T¹ is —OR³ or —SR³ wherein R¹, R² and R³ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or

[0038] R¹and R³, and R² and R³ each taken together with the adjacent heteroatom form 5- to 7-membered ring;

[0039] its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.

[0040] VI) a compound described in V), represented by the formula (VI):

[0041] wherein Q² is —NR⁸R⁹, —OR⁸, or —SR⁸, T² is —OR¹⁰ or —SR¹⁰ wherein R⁸, R⁹ and R¹⁰ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro;

[0042] W is —O—, —S—, or —N(R^(A))— wherein R^(A) is hydrogen atom or optionally substituted alkyl;

[0043] R⁵, R⁶, R^(F), R^(G), X, and Z are as defined above mentioned V);

[0044] its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.

[0045] In the case of R⁸ and R¹⁰ are bonded directly with O or S, R⁸ and R¹⁰ peferably are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, non-aromatic heterocyclic group, or acyl;

[0046] VII) a compound described in V), represented by the formula (VII):

[0047] wherein R⁵, R⁶, R^(F), R^(G), and Z are as defined above mentioned V);

[0048] Q² and T² are as defined above mentioned VI)

[0049] its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.

[0050] VIII) a compound described in V), represented by the formula (VIII):

[0051] wherein R¹² is hydrogen or alkyl;

[0052] R^(H) and R^(J) are each independently hydrogen atom or alkyl;

[0053] V is optically substituted aryl;

[0054] the other symbols are as defined above mentioned VI);

[0055] its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.

[0056] IX) a compound, its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate as described in any one of the above I) to V), wherein R¹, R², R³, and R⁴ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl,

[0057] X) a compound, its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate as described in any one of the above VI) to VIII), wherein R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl,

[0058] XI) a pharmaceutical composition which contains as active ingredient a compound as described in any one of I) to X),

[0059] XII) a pharmaceutical composition for use as an antitumor agent which contains as active ingredient a compound as described in any one of I) to X),

[0060] XIII) a pharmaceutical composition for use as a cytostatic agent which contains as described in any one of I) to X),

[0061] XIV) a pharmaceutical composition for use as an inhibitor against a signal derived from Ras oncogene products which contains as active ingredient a compound as described in any one of I) to X),

[0062] XV) use of a compound of any one of I) to X) for the preparation of a pharmaceutical composition for treating cancer, and

[0063] XVI) a method of treating a mammal, including a human, to alleviate a pathological effect of cancer, which comprises administration to the mammal of a compound as described in any one of I) to X).

[0064] The term “alkyl” employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 1 to 8 carbon atoms. Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. Preferably, C1 to C6 alkyl is exemplified. More preferably, C1 to C3 alkyl is exemplified.

[0065] The term “alkenyl” employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more double bonds. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, prenyl, a variety of butenyl isomers and the like. Preferably, C2 to C6 alkenyl is exemplified. More preferably, C2 to C3 alkenyl is exemplified.

[0066] The term “alkynyl” employed alone or in combination with other terms in the present specification includes a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more triple bonds. The alkynyl may contain (a) double bond(s). An example of the alkenyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, and the like. Preferably, C2 to C6 alkynyl is exemplified. More preferably, C2 to C3 alkynyl is exemplified.

[0067] The term “aryl” employed alone or in combination with other terms in the present specification includes a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Preferably, phenyl, 1-naphthyl, and 2-naphthyl are exemplified. More preferably, phenyl is exemplified.

[0068] The term “aralkyl” in the present specification includes a group wherein the above-mentioned “alkyl” is substituted with the above-mentioned “aryl”. An example of aralkyl includes benzyl, phenethyl (e.g., 2-phenylethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl), anthrylmethyl (e.g., 9-anthrylmethyl) and the like. Preferably, benzyl and phenylethyl are exemplified.

[0069] The term “heteroaryl” employed alone or in combination with other terms in the present specification includes a 5- to 6-membered aromatic cyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and may be fused with the above mentioned “aryl”, the later mentioned “carbocyclic group”, and “non-aromatic heterocyclic group”, or “heteroaryl”. Heteroaryl is bonded at any possible position when the heteroaryl is a condensed ring. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 3-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4-imidazolyl), pyrazolyl (e.g., 3-pyrazolyl and 5-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 3-pyridyl and 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 4-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 2-furyl and 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl and 3-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), oxazolyl, thiadiazolyl (e.g., 1,3,4-thiadiazolyl and 1,2,4-thiadiazolyl), 4H-1,2,4-triazolyl, quinoxalinyl, 2-pyridon-3-yl, and the like. Preferably, pyridyl, pyrazinyl, furyl, thienyl and the like are exemplified.

[0070] The term “5-membered heteroaryl-diyl” herein used includes a 5-membered divalent group derived from above-mentioned “heteroaryl”. Examples of the 5-membered heteroaryl-diyl are furan-2,5-diyl, thiophene-2,5-diyl, pyrrole-2,5-diyl, pyrazole-3,5-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole3,5-diyl, oxazole-3,5-diyl, isoxazole-3,5-diyl, 1,3,4-thiadiazole-3,5-diyl, 1,2,4-thiadiazole-3,5-diyl, 4H-1,2,4-triazole-3,5-diyl, and the like.

[0071] The term “non-aromatic heterocyclic group” employed alone or in combination with other terms in the present specification includes a 5- to 7-membered non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and a cyclic group wherein two or more of the above-mentioned heterocyclic groups are fused. Examples of the heterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl), piperidinyl (e.g., piperidino and 2-piperidinyl), piperazinyl (e.g., 1-piperazinyl), morpholinyl (e.g., morpholino and 3-morpholinyl), and the like.

[0072] The term “5-membered non-aromatic heterocycle-diyl” herein used includes a 5-membered divalent group derived from the above-mentioned “non-aromatic heterocyclic group”. Examples of the 5-membered non-aromatic heterocycle-diyl are pyrrolidindiyl (e.g., pyrrolidine-2,5-diyl) and the like.

[0073] The term “carbocyclic group” herein used includes a 3- to 7-membered non-aromatic carbocyclic group. Examples of the carbocyclic group are cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl), cycloalkenyl (e.g., cyclopentenyl and cyclohexenyl), and the like.

[0074] In this specification, examples of the ring represented by “R¹and R², and R³ and R⁴ each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered non-aromatic heterocyclic ring optionally containing O, N, or S” are aziridine, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, pyrazolidine, pyrrole, pyrimidine, triazine, azepine, perhydroazepine, and the like.

[0075] In this specification, examples of the ring represented by “R² and R³ each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered non-aromatic heterocyclic ring optionally containing O, N, or S” are imidazolidine, hexahydropyridine, and perhydro-1,3-diazepine the like.

[0076] In this specification, examples of the ring represented by “R¹and R³, or R² and R³ each taken together with heteroatom form 5- to 7-membered non-aromatic heterocyclic ring optionally containing O, N, or S” are thiazolidine, perhydro-1,3-thiadine, oxazolidine, perhydro-1,3-oxadine, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane, 1,3-oxathiane, perhydro-1,3-oxazepine, perhydro-1,3-thiazepine, and the like.

[0077] The term “acyl” employed alone or in combination with other terms in the present specification includes alkylcarbonyl of which alkyl part is the above-mentioned “alkyl” and arylcarbonyl of which aryl part is the above-mentioned “aryl”. Examples of the acyl are acetyl, propanoyl, benzoyl, and the like.

[0078] The term “halogen” herein used means fluoro, chloro, bromo, and iodo.

[0079] Examples of “alkyloxy” herein used are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and the like. Preferably, methyloxy, ethyloxy, n-propyloxy, and isopropyloxy are exemplified.

[0080] Examples of “alkylthio” herein used are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like. Preferably, methylthio, ethylthio, n-propylthio, and isopropylthio are exemplified.

[0081] Examples of “alkyloxycarbonyl” herein used are methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, and the like.

[0082] The term “optionally substituted amino” herein used means amino substituted with one or two of the above-mentioned “alkyl”, the above-mentioned “aralkyl”, the above-mentioned “acyl”, optionally substituted arylsulfonyl (e.g., alkyloxyphenylsulfonyl), arylalkylene (e.g., benzylidene), alkylsulfonyl, carbamoyl and the like or non-substituted amino. Examples of the optionally substituted amino are amino, methylamino, ethylamino, dimethylamino, ethylmethylamino, diethylamino, benzylamino, benzoylamino, acetylamino, propionylamino, tert-butyloxycarbonylamino, benzylidenamino, methylsulfonylamino, 4-methoxyphenylsulfonylamino, and the like. Preferably, amino, methylamino, dimethylamino, diethylamino, acetylamino are exemplified.

[0083] Substituents on the aromatic ring of “optionally substituted aralkyl” are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, and cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy), optionally substituted amino (e.g., amino, methylamino, dimethylamino, diethylamino, and benzylidenamino), alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and neopentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), formyl, lower alkanoyl (e.g., acetyl and propionyl), acyloxy (e.g., acetyloxy), acylamino, alkylsulfonyl (e.g., methylsulfonyl), and the like. These substituents may be substituted at one or more possible position(s).

[0084] Substituents of “optionally substituted alkyl”, “optionally substituted alkyloxy”, and “optionally substituted alkyloxycarbonyl” are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., amino, methylamino, dimethylamino, carbamoylamino, and tert-butyloxycarbonylamino), acyloxy (e.g., acetyloxy), optionally substituted aralkyloxy (e.g., benzyloxy and 4-methyloxybenzyloxy), and the like. These substituents may be substituted at one or more possible position(s).

[0085] Substituents of “optionally substituted alkenyl” and “optionally substituted alkynyl” are, for example, hydroxy, alkyloxy (e.g., methyloxy and ethyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl and ethyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), optionally substituted amino (e.g., amino, methylamino, dimethylamino, carbamoylamino, and tert-butyloxycarbonylamino), acyloxy (e.g., acetyloxy), optionally substituted aralkyloxy (e.g., benzyloxy and 4-methyloxybenzyloxy), optionally substituted aryl (e.g., phenyl), and the like. These substituents may be substituted at one or more possible position(s).

[0086] The preferable examples of “optionally substituted alkyl” are methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyclohexylmethyl, carboxyethyl, acetyloxyethyl, and benzyloxymethyl. More preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, 2,2,2-trifluoroethyl are exemplified.

[0087] Substituents of “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted 5-membered heteroaryl-diyl”, “optionally substituted 5-membered non-aromatic heterocycle-diyl”, and “an optionally substituted non-aromatic heterocyclic group” are, for example, hydroxy, optionally substituted alkyloxy (e.g., methyloxy, ethyloxy, n-propyloxy, isopropyloxy, ethyloxycarbonylmethyloxy, carboxymethyloxy and 4-methoxybenzyloxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkyloxycarbonyl (e.g., methyloxycarbonyl, ethyloxycarbonyl, and tert-butyloxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy), optionally substituted amino (e.g., amino, methylamino, dimethylamino, ethylamino, diethylamino, acetylmethylamino, benzylidenamino, 4-methoxyphenylsulfonylamino, methylsulfonylamino, benzoylamino, acetylamino, propionylamino, and tert-butyloxycarbonylamino), optionally substituted sulfamoyl (e.g., sulfamoyl), optionally substituted alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, t-butyloxycarbonylaminomethyl, and aminomethyl), alkenyl (e.g., vinyl, propenyl, and prenyl), optionally substituted alkynyl (e.g., ethynyl and phenylethynyl), alkenyloxy (e.g., propenyloxy and prenyloxy), formyl, acyl (e.g., acetyl, propionyl, and benzoyl), acyloxy (e.g., acetyloxy), optionally substituted carbamoyl (e.g., carbamoyl and N,N-dimethylcarbamoyl), alkylsulfonyl (e.g., methylsulfonyl), aryl (e.g., phenyl), aralkyl (e.g., benzyl), carbothioamide, optionally substituted heterocyclic group (e.g., dioxolanyl, 2-methyl-1,3-dioxolan-2-yl, pyrrolidinyl, and piperidino), optionally substituted heteroaryl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridine N-oxide-4-yl, 1-methyl-2-pyridon-4-yl, 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), and the like. These substituents may be substituted at one or more possible position(s). Preferably, optionally substituted amino, halogen, nitro, alkyl, and alkyloxy are exemplified.

[0088] Examples of “optionally substituted aryl” are phenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-acetylaminophenyl, 4-acetylaminophenyl, 2-benzoylaminophenyl, 4-benzoylaminophenyl, 2-methylsulfonylaminophenyl, 2-propionylaminophenyl, 2-methylaminophenyl, 4-methylaminophenyl, 2-dimethylaminophenyl, 4-dimethylaminophenyl, 2-ethylaminophenyl, 4-ethylaminophenyl, 4-diethylaminophenyl, 2-(4-methoxyphenylsulfonylamino)phenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 2-ethyloxycarbonylmethyloxyphenyl, 2-carboxymethyloxyphenyl, 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 4-methylphenyl, 4-methyloxyphenyl, 4-ethyloxyphenyl, 4-n-propyloxyphenyl, 4-isopropyloxyphenyl, 4-tert-butyloxycarbonylphenyl, 4-prenyloxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 4-(4-methoxybenzyloxy)phenyl, 4-methyloxycarbonylphenyl, 4-sulfamoylphenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-carboxyphenyl, 4-biphenylyl, 4-benzoylphenyl, 4-pyrrolidinophenyl, 4-piperidinophenyl, 3-aminonaphthalen-2-yl, 2-amino-5-chlorophenyl, 2-amino-3-chlorophenyl, 2-amino-4-chlorophenyl, 2-amino-6-chlorophenyl, 4-amino-2-chlorophenyl, 2-amino-4-fluorophenyl, 2-amino-5-fluorophenyl, 2-amino-6-fluorophenyl, 4-amino-2-fluorophenyl, 2-amino-4,5-difluorophenyl, 2-amino-3-methylphenyl, 2-amino-4-methylphenyl, 2-amino-5-methylphenyl, 2-amino-6-methylphenyl, 4-amino-3-methylphenyl, 4-amino-3-methyloxyphenyl, 2-amino-4-nitrophenyl, 4-amino-3-hydroxyphenyl, 2-amino-4-carboxyphenyl, 2-amino-4-methyloxycarbonylphenyl, 4-amino-2-hydroxyphenyl, 4-amino-3-(4-methoxybenzyloxy)phenyl, 2,4-diaminophenyl, 3,4-diaminophenyl, 2-acetylmethylaminophenyl, 2-acetylamino-4-fluorophenyl, 2-acetylamino -4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-amino-2-methylphenyl, 2-fluoro-4-nitrophenyl, 4-amino-2-methyloxyphenyl, 2-methyloxy-4-nitrophenyl, 4-fluoro-2-nitrophenyl, 4-amino-2-trifluoromethylphenyl, 4-amino-2-ethyloxyphenyl, 4-amino-2-trifluoromethyloxyphenyl, 2-chloro-4-nitrophenyl, 2-methyl-4-nitrophenyl, 4-nitro-2-trifluoromethyloxyphenyl, 4-nitro-2-trifluoromethylphenyl, 2-ethyloxy-4-nitrophenyl, and the like.

[0089] Examples of “optionally substituted heteroaryl” are pyridin-3-yl, 2-aminopyridin -3-yl, 2-aminopyridin-5-yl, 3-aminopyrazin-2-yl, 3-aminopyrazol-4-yl, 4-amino-2-methylpyrimidin-5-yl, 2-aminothiophen-3-yl, 3-methylthiophen-2-yl, 5-methylthiophen-2-nyl, furan-2-yl, furan-3-yl, 2-methylfuran-3-yl, 2,5-dimethylfuran-3-yl, 5-bromofuran-2-yl, 2-nitrofuran-4-yl, 1-methyl-4-nitropyrazol-3-yl, 1-methyl-4-nitropyrazol-5-yl, 5-nitropyrazol-3-yl, 4-nitropyrazol-3-yl, 2-(3-pyridyl)thiazol-4-yl, 2-(4-pyridyl)thiazol-4-yl, 6-(1-pyrrolyl)pyridin-3-yl, N-methyl-2-pyridon-3-yl, and the like.

[0090] Examples of “optionally substituted 5-membered heteroaryl-diyl” are furan-2,5-diyl, thiophene-2,5-diyl, pyrrole-2,5-diyl, pyrazole-3,5-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, oxazole-2,5-diyl, isooxazole-3,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,2,4-thiadiazole-3,5-diyl, 4H-1,2,4-triazole-3,5-diyl, 1-methylpyrazole-3,5-diyl, and the like.

[0091] Preferable examples of R¹ to R⁶, R^(B), R^(C), X, Y, and Z of the compound represented by the formula (I) are shown below as groups (a) to (t).

[0092] R¹and R² are (a) one is hydrogen atom, the other is optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro.

[0093] R³ and R⁴ are (b) each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; (c) each independently hydrogen atom, alkyl optionally substituted with halogen atom, alkenyl, or alkynyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; and (d) one is hydrogen atom and the other is alkyl optionally substituted with halogen, alkenyl, or alkynyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro.

[0094] R⁵ is (e) hydrogen atom, alkyloxy, alkylthio, or optionally substituted alkyl; (f) hydrogen atom or alkyl; and (g) hydrogen atom or C1 to C2 alkyl.

[0095] R⁶ is (h) hydrogen atom or alkyl; and (i) hydrogen atom.

[0096] X is (j) —O— or —S—; and (k) —S—.

[0097] Y is (1) 5-membered heteroaryl-diyl; (m) 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, 1,3,4-thiadiazole-2,5-diyl, or 1,2,4-thiadiazole-3,5-diyl; and (n) 1,3,4-oxadiazole-2,5-diyl.

[0098] Z is (O) optionally substituted aryl or optionally substituted heteroaryl; (p) optionally substituted phenyl or optionally substituted monocyclic heteroaryl; and (q) phenyl, pyridyl, thienyl, or furyl, which are substituted with 1 to 3 substituents selected from the group consisting of optionally substituted amino, halogen, alkyl, alkyloxy, acyl, phenyl, alkyloxycarbonyl, hydroxy, nitro, or haloalkyl.

[0099] A preferable example of R^(B) and R^(C) is (r) (R^(B), R^(C)) is (alkyl, hydrogen atom) or (hydrogen atom, hydrogen atom); and (s) (R^(B), R^(C)) is (hydrogen atom, hydrogen atom).

[0100] A preferred group of compounds represented by the formula (I) is shown below.

[0101] [(R¹, R²), (R³, R⁴), R⁵, R⁶, X, Y, (R^(B), R^(C))]=[a, b, e, h, j, l, r], [a, b, e, h, j, l, s], [a, b, e, h, j, m, r], [a, b, e, h, j, m, s], [a, b, e, h, j, n, r], [a, b, e, h, j, n, s], [a, b, e, h, k, l, r], [a, b, e, h, k, l, s], [a, b, e, h, k, m, r], [a, b, e, h, k, m, s], [a, b, e, h, k, n, r], [a, b, e, h, k, n, s], [a, b, e, i, j, l, r], [a, b, e, i, j, l, s], [a, b, e, i, j, m, r], [a, b, e, i, j, m, s], [a, b, e, i, j, n, r], [a, b, e, i, j, n, s], [a, b, e, i, k, l, r], [a, b, e, i, k, l, s], [a, b, e, i, k, m, r], [a, b, e, i, k, m, s], [a, b, e, i, k, n, r], [a, b, e, i, k, n, s], [a, b, f, h, j, l, r], [a, b, f, h, j, l, s], [a, b, f, h, j, m, r], [a, b, f, h, j, m, s], [a, b, f, h, j, n, r], [a, b, f, h, j, n, s], [a, b, f, h, k, l, r], [a, b, f, h, k, l, s], [a, b, f, h, k, m, r], [a, b, f, h, k, i, s], [a, b, f, h, k, n, r], [a, b, f, h, k, n, s], [a, b, f, i, j, l, r], [a, b, f, i, j, l, s], [a, b, f, i, j, m, r], [a, b, f, i, j, m, s], [a, b, f, i, j, n, r], [a, b, f, i, j, n, s], [a, b, f, i, k, l, r], [a, b, f, i, k, l, s], [a, b, f, i, k, m, r], [a, b, f, i, k, m, s], [a, b, f, i, k, n, r], [a, b, f, i, k, n, s], [a, b, g, h, j, l, r], [a, b, g, h, j, l, s], [a, b, g, h, j, m, r], [a, b, g, h, j, m, s], [a, b, g, h, j, n, r], [a, b, g, h, j, n, s], [a, b, g, h, k, l, r], [a, b, g, h, k, l, s], [a, b, g, h, k, l, r], [a, b, g, h, k, m, s], [a, b, g, h, k, n, r], [a, b, g, h, k, n, s], [a, b, g, i, j, l, r], [a, b, g, i, j, l, s], [a, b, g, i, j, m, r], [a, b, g, i, j, m, s], [a, b, g, i, j, n, r], [a, b, g, h, j, n, r], [a, b, g, i, k, l, r], [a, b, g, i, k, l, s], [a, b, g, i, k, m, r], [a, b, g, i, k, m, s], [a, b, g, i, k, n, r], [a, b, g, i, k, n, s], [a, c, e, h, j, l, r], [a, c, e, h, j, l, s], [a, c, e, h, j, m, r], [a, c, e, h, j, m, s], [a, c, e, h, j, n, r], [a, c, e, h, j, n, s], [a, c, e, h, k, l, r], [a, c, e, h, k, l, s], [a, c, e, h, k, m, r], [a, c, e, h, k, m, s], [a, c, e, h, k, n, r], [a, c, e, h, k, n, s], [a, c, e, i, j, l, r], [a, c, e, i, j, l, s], [a, c, e, i, j, m, r], [a, c, e, i, j, m, s], [a, c, e, i, j, n, r], [a, c, e, i, j, n, s], [a, c, e, i, k, l, r], [a, c, e, i , k, l, s], [a, c, e, i , k, m, r], [a, c, e, i, k, m, s], [a, c, e, i, k, n, r], [a, c, e, i, k, n, s], [a, c, f, h, i, j, l, r], [a, c, f, h, j, l, m, s], [a, c, f, h, j, m, r], [a, c, f, h, j, m, s], [a, c, e, f, h, j, n, r], [a, c, f, h, j, n, s], [a, c, f, h, k, l, r], [a, c, f, h, k, l, s], [a, c, f, h, k, m, r], [a, c, f, h, k, m, s], [a, c, f, h, k, n, r], [a, c, f, h, k, n, s], [a, c, f, i, j, l, r], [a, c, f, i, j, l, s], [a, c, f, i, j, m,r], [a, c, f, i, j, m, s], [a, c, f, i, j, n,r], [a, c, f, i, j, n, s], [a, c, f, i, k, l, r], [a, c, f, i, k, l, s], [a, c, f, i, k, m, r], [a, c, f, i, k, m, s], [a, c, f, i, k, n, r], [a, c, f, i, k, n, s], [a, c, g, h, j, l, r], [a, c, g, h, j, l, s], [a, c, g, h, j, m, r], [a, c, g, h, j, m, s], [a, c, g, h, j, n, r], [a, c, g, h, j, n, s], [a, c, g, h, k, l, r], [a, c, g, h, k, l, s], [a, c, g, h, k, m, r], [a, c, g, h, k, m, s], [a, c, g, h, k, n, r], [a, c, g, h, k, n, s], [a, c, g, i, j, l, r], [a, c, g, i, j, l, s], [a, c, g, i, j, m, r], [a, c, g, i, j, m, s], [a, c, g, i, j, n, r], [a, c, g, i, j, n, s], [a, c, g, i, k, l, r], [a, c, g, i, k, l, s], [a, c, g, i, k, m, r], [a, c, g, i, k, m, s], [a, c, g, i, k, n, r], [a, c, g, i, k, n, s], [a, d, e, h, j, l, r], [a, d, e, h, j, l, s], [a, d, e, h, j, m, r], [a, d, e, h, j, m, s], [a, d, e, h, j, n, r], [a, d, e, h, j, n, s], [a, d, e, h, k, l, r], [a, d, e, h, k, l, s], [a, d, e, h, k, m, r], [a, d, e, h, k, m, s], [a, d, e, h, k, n, r], [a, d, e, h, k, n, s], [a, d, e, i, j, l, r], [a, d, e, i, j, l, s], [a, d, e, i, j, m, r], [a, d, e, i, j, m, s], [a, d, e, i, j, n, r], [a, d, e, i, j, n, s], [a, d, e, i, k, l, r], [a, d, e, i, k, l, s], [a, d, e, i, k, m, r], [a, d, e, i, k, m, s], [a, d, e, i, k, n, r], [a, d, e, i, k, n, s], [a, d, f, h, j, l, r], [a, d, f, h, j, l, s], [a, d, f, h, j, m, r], [a, d, f, h, j, m, s], [a, d, f, h, j, n, r], [a, d, f, h, j, n, s], [a, d, f, h, k, l, r], [a, d, f, h, k, l, s], [a, d, f, h, k, m, r], [a, d, f, h, k, m, s], [a, d, f, h, k, n, r], [a, d, f, h, k, n, s], [a, d, f, i, j, l, r], [a, d, f, i, j, l, s], [a, d, f, i, j, m, r], [a, d, f, i, j, m, s], [a, d, f, i, j, n, r], [a, d, f, i, j, n, s], [a, d, f, i, k, l, r], [a, d, f, i, k, l, s], [a, d, f, i, k, m, r], [a, d, f, i, k, m, s], [a, d, f, i, k, n, r], [a, d, f, i, k, n, s], [a, d, g, h, j, l, r], [a, d, g, h, j, l, s], [a, d, g, h, j, m, r], [a, d, g, h, j, m, s], [a, d, g, h, j, n, r], [a, d, g, h, j, n, s], [a, d, g, h, k, l, r], [a, d, g, h, k, l, s], [a, d, g, h, k, m, r], [a, d, g, h, k, m, s], [a, d, g, h, k, n, r], [a, d, g, h, k, n, s], [a, d, g, i, j, l, r], [a, d, g, i, j, l, s], [a, d, g, i, j, m, r], [a, d, g, i, j, m, s], [a, d, g, i, j, n, r], [a, d, g, i, j, n, s], [a, d, g, i, k, l, r], [a, d, g, i, k, l, s], [a, d, g, i, k, m, s], [a, d, g, i, k, n, r], [a, g, i, k, n, s]

[0102] Preferred embodiments of this invention are compounds wherein Z is any one of (o) to (q) and [(R¹, R²), (R³, R⁴), R⁵, R⁶, X, Y, (R^(B), R^(C))] is any one of the above combinations.

[0103] Preferable examples of R⁵, R⁶, R^(F), R^(G), Q¹, T¹, X, Y, and Z of the compound represented by the formula (V) are shown below as groups (a) to (r).

[0104] R⁵ is (a) hydrogen atom, alkyloxy, alkylthio, or optionally substituted alkyl; (b) hydrogen atom or alkyl; and (c) hydrogen atom or C1 to C2 alkyl.

[0105] R³ is (d) hydrogen atom or alkyl; and (e) hydrogen atom.

[0106] A preferable example of R^(F) and R^(G) is (f) (R^(B), R^(C)) is (hydrogen atom, hydrogen atom), (hydrogen atom, alkyl), (alkyl, alkyl), or (hydrogen atom, alkyloxy); and (g) is (hydrogen atom, hydrogen atom), (hydrogen atom, alkyl), or (alkyl, alkyl).

[0107] Q¹ and T¹ are (h) Q¹ is —NR¹R² or —SR¹ wherein R¹ and R² are each independently hydrogen atom, optionally substituted alkyl, alkenyl, or alkynyl, T¹ is —SR³ wherein R³ is hydrogen atom, optionally substituted alkyl, alkenyl, or alkynyl; (i) Q¹ is —NR¹R² or —SR¹ wherein R¹and R² are each independently hydrogen atom, alkyl optionally substituted with halogen, alkenyl, or alkynyl, T¹ is —SR³ wherein R³ is hydrogen atom, alkyl optionally substituted with halogen, alkenyl, or alkynyl; (j) Q¹ is —NR¹R² or —SR¹ wherein R¹ and R² are one is hydrogen atom and the other is C1 to C3 alkyl optionally substituted with halogen, T¹ is —SR³ wherein R³ is hydrogen atom or alkyl optionally substituted with halogen.

[0108] X is (k) —O— or —S—; and (1) —S—.

[0109] Y is (m) 5-membered heteroaryl-diyl; (n) 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, 1,3,4-thiadiazole-2,5-diyl, or 1,2,4-thiadiazole-3,5-diyl; and (0) 1,3,4-oxadiazole-2,5-diyl.

[0110] Z is (p) optionally substituted aryl or optionally substituted heteroaryl; (q) optionally substituted phenyl or optionally substituted monocyclic heteroaryl; and (r) phenyl, pyridyl, thienyl, or furyl, which are substituted with 1 to 3 substituents selected from the group consisting of optionally substituted amino, halogen, alkyl, alkyloxy, acyl, phenyl, alkyloxycarbonyl, hydroxy, nitro, or haloalkyl.

[0111] A preferred group of compounds represented by the formula (V) is shown below.

[0112] [R⁵, R⁶, (R^(F), R^(G)), (Q¹, T¹), X, Y]=[a, d, f, h, k, m], [a, d, f, h, k, n], [a, d, f, h, k, o], [a, d, f, h, l, m], [a, d, f, h, l, n], [a, d, f, h, l, o], [a, d, f, i, k, m], [a, d, f, i, k, n], [a, d, f, i, k, o], [a, d, f, i, l, m], [a, d, f, i, l, n], [a, d, f, i, l, o], [a, d, f, j, k, m], [a, d, f, j, k, n], [a, d, f, j, k, o], [a, d, f, j, l, m], [a, d, f, j, l, n], [a, d, f, j, l, o], [a, d, g, h, k, m], [a, d, , h, k, n], [a, d, g, h, k, o], [a, d, h, l, m], [a, d, g, h, l, n], [a, d, g, h, l, o], [a, d, g, i, k, m], [a, d, g, i, k, n], [a, d, g, i, k, o], [a, d, g, i, l, m], [a, d, g, i, l, n], [a, d, g, i, l, o], [a, d, g, j, k, m], [a, d, g, j, k, n], [a, d, g, j, k, o], [a, d, g, j, l, m], [a, d, g, j, l, n], [a, d, g, j, l, o], [a, e, f, h, k, m], [a, e, f, h, k, n], [a, e, f, h, k, o], [a, e, f, h, l, m], [a, e, f, h, l, n], [a, e, f, h, l, o], [a, e, f, i, k, m], [a, e, f, i, k, n], [a, e, f, i, k, o], [a, e, f, i, l, m], [a, e, f, i, l, n], [a, e, f, i, l, o], [a, e, f, j, k, m], [a, e, f, j, k, n], [a, e, f, j, k, o], [a, e, f, j, l, m], [a, e, f, j, l, n], [a, e, f, j, l, o], [a, e, g, h, k, m], [a, e, g, h, k, n], [a, e, g, h, k, o], [a, e, g, h, l, m], [a, e, g, h, l, n], [a, e, g, h, l, o], [a, e, g, i, k, m], [a, e, g, i, k, n], [a, e, g, i, k, o], [a, e, g, i, l, m], [a, e, g, i, l, n], [a, e, g, i, l, o], [a, e, g, j, k, m], [a, e, g, j, k, n], [a, e, g, j, k, o], [a, e, g, j, l, m], [a, e, g, j, l, n], [a, e, g, j, l, o], [b, d, f, h, k, m], [b, d, f, h, k, n], [b, d, f, h, k, o], [b, d, f, h, l, m], [b, d, f, h, l, n], [b, d, f, h, l, o], [b, d, f, i, k, m], [b, d, f, i, k, n], [b, d, f, i, k, o], [b, d, f, i, l, m], [b, d, f, i, l, n], [b, d, f, i, l, o], [b, d, f, j, k, m], [b, d, f, j, k, n], [b, d, f, j, k, o], [b, d, f, j, l, m], [b, d, f, j, l, n], [b, d, f, j, l, o], [b, d, g, h, k, m], [b, d, g, h, k, n], [b, d, g, h, k, o], [b, d, g, h, l, m], [b, d, g, h, l, n], [b, d, g, h, l, o], [b, d, g, i, k, m], [b, d, g, i, k, n], [b, d, g, i, k, o], [b, d, g, i, l, m], [b, d, g, i, l, n], [b, d, g, i, l, o], [b, d, g, j, k, m], [b, d, g, j, k, n], [b, d, g, j, k, o], [b, d, g, j, l, m], [b, d, g, j, l, n], [b, d, g, j, l, o], [b, e, f, h, k, m], [b, e, f, h, k, n], [b, f, h, k, o], [b, e, f, h, l, m], [b, e, f, h, l, n], [b, e, f, h, l, o], [b, e, f, i, k, m], [b, e, f, i, k, n], [b, e, f, i, k, o], [b, e, f, i, l, m], [b, e, f, i, l, n], [b, e, f, i, l, o], [b, e, f, j, k, m], [b, e, f, j, k, n], [b, e, f, j, k, o], [b, e, f, j, l, m], [b, e, f, j, l, n], [b, e, f, j, l, o], [b, e, g, h, k, m], [b, e, g, h, k, n], [b, e, g, h, k, o], [b, e, g, h, l, m], [b, e, g, h, l, n], [b, e, g, h, l, o], [b, e, g, i, k, m], [b, e, g, i, k, n], [b, e, g, i, k, o], [b, e, g, i, l, m], [b, e, g, i, l, n], [b, e, g, i, l, o], [b, e, g, ,k, m], [b, e, g, j, k, n], [b, e, g, j, k, o], [b, e, g, j, l, m], [b, e, g, j, l, n], [b, e, g, j, l, o], [c, d, f, h, k, m], [c, d, f, h, k, n], [c, d, f, h, k, o], [c, d, f, h, l, m], [c, d, f, h, l, n], [c, d, f, h, l, o], [c, d, f, i, k, m], [c, d, f, i, k, n], [c, d, f, i, k, o], [c, d, f, i, l, m], [c, d, f, i, l, n], [c, d, f, i, l, o], [c, d, f, j, k, m], [c, d, f, j, k, n], [c, d, f, j, k, o], [c, d, f, j, l, m], [c, d, f, j, l, n], [c, d, f, j, l, o], [c, d, g, h, k, m], [c, d, g, h, k, n], [c, d, g, h, k, o], [c, d, g, h, l, m], [c, d, g, h, l, n], [c, d, g, h, l, o], [c, d, i, k, m], [c, d, g, i, k, n], [c, d, g, i, k, o], [c, d, g, i, l, m], [c, d, g, i, l, n], [c, d, g, i, l, o], [c, d, g, j, k, m], [c, d, g, j, k, n], [c, d, g, j, k, o], [c, d, g, j, l, m], [c, d, g, j, l, n], [c, d, g, j, l, o], [c, e, f, h, k, m], [c, e, f, h, k, n], [c, e, f, h, k, o], [c, e, f, h, l, m], [c, e, f, h, l, n], [c, e, f, h, l, o], [c, e, f, i, k, m], [c, e, f, i, k, n], [c, e, f, i, k, o], [c, e, f, i, l, m], [c, e, f, i, l, n], [c, e, f, i, l, o], [c, e, f, j, k, m], [c, e, f, j, k, n], [c, e, f, j, k, o], [c, e, f, j, l, m], [c, e, f, j, l, n], [c, e, f, j, l, o], [c, e, g, h, k, m], [c, e, g, h, k, n], [c, e, g, h, k, o], [c, e, g, h, l, m], [c, e, g, h, l, n], [c, e, g, h, l, o], [c, e, g, i, k, m], [c, e, g, i, k, n], [c, e, g, i, k, o], [c, e, g, i, l, m], [c, e, g, i, l, n], [c, e, g, i, l, o], [c, e, g, j, k, m], [c, e, g, j, k, n], [c, e, g, j, k, o], [c, e, g, j, l, m], [c, e, g, j, l, n], [c, e, g, j, l, o]

[0113] Preferred embodiments of this invention are compounds wherein Z is any one of (p) to (r) and [R⁵, R⁶, (R^(F), R^(G)), (Q¹, T¹), X, Y] is any one of the above combinations.

[0114] In this specification, the compounds represented by the formula (I) may be represented by the below formula.

[0115] The compounds represented by the formula (II), (III), and (IV) are as well as the above.

[0116] In this specification, a compound of formula (I) wherein R¹ is hydrogen atom may be represented as an isomer of the formula (IX).

[0117] wherein R², R³, R⁴, R⁵, R⁶, R^(B), R^(C), X, Y, and Z are as defined above; R¹ is hydrogen atom.

[0118] The compounds represented by the formula (II), (III), and (IV) are as well as the above.

[0119] In this specification, a compound of formula (V) wherein T¹ is —SR³ wherein R³ is hydrogen atom may be represented as an isomer of the formula (X). The compounds wherein T¹ is —OR³ wherein R³ is hydrogen atom are as well as the above.

[0120] wherein R⁵, R⁶, R^(F), R^(G), Q¹, X, Y, and Z are as defined above; R³ is hydrogen atom.

[0121] The compounds represented by the formulae (VI), (VII), and (VIII) are as well as the above.

[0122] In this specification, according to alkylation conditions for synthesis of the compounds (V) wherein T¹ is —SR³ wherein R³ is alkyl, the compounds represented by the formula (X) may be obtained. The compounds wherein T¹ is —OR³ wherein R³ is alkyl are as well as the above.

[0123] wherein R⁵, R⁶, R^(F), R^(G), Q¹, X, Y, and Z are as defined above; R³ is alkyl.

[0124] The compounds represented by the formulae (VI), (VII), and (VIII) are as well as the above.

[0125] In this specification, the compounds of formula (I) wherein R^(B) and R^(C) are different, are represented as an optical active compound by the formulae (I′) and (I″).

[0126] wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(B), R^(C), X, Y, and Z are as defined above.

[0127] The compounds represented by the formulae (II), (III), (IV), (V), (VI), (VII), and (VIII) are as well as the above.

BEST MODE FOR CARRYING OUT THE INVENTION

[0128] The compounds of the present invention represented by the formulae (I), (V), or (XIII) can be synthesized by the well-known methods described in a literature of chemistry. A summary of the useful methods for synthesis of the compounds of the present invention is shown below.

[0129] (Synthetic Method)

[0130] wherein R⁵, R⁶, R^(B), R^(C), X, Y, and Z are as defined above; R¹³ is a protective group of a hydroxy group such as methyl, ethyl, trimethylsilyl, and tert-butyldimethylsilyl or hydrogen atom; Q³ is —NR¹R², —OR¹, or —SR¹; T³ is —NR³R⁴, —OR¹, or —SR¹ wherein R¹, R², R³, and R⁴ are as defined above.

[0131] The compound represented by the formula (XIII) can be synthesized by reacting Z-Y-XH (XI) with the pyrimidine derivatives (XII) mentioned later such as (XII-1) to (XII-4). The pyrimidine derivatives (XII) in a solvent such as water, acetic acid, and pyridine are treated with a hydrohalogenic acid such as hydrochloric acid and hydrobromic acid to give hydrogen halide salts of 5-halogenomethylpyrimidine. When R¹³ is hydrogen atom, a halogenation agent such as thionyl halide and phosphorous halide can be used. The obtained salts and Z-Y-XH (XI) in a solvent such as water, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, and tetrahydrofuran are reacted with an appropriate base, for example an inorganic base such as sodium hydroxide, potassium butoxide, sodium hydride, potassium hydride, and potassium carbonate or an organic base such as triethylamine, pyridine, and diisopropylethylamine at −20° C. to 100° C., preferably 0° C. to 30° C. for 1 min to 24 h, preferably 10 min to 12 h to give the aimed compound (XIII).

[0132] Compound (XI) and compound (XII) can be synthesized by the methods A to I and the methods J to N as shown below.

[0133] In the methods A to I, Z represents optionally substituted aryl or optionally substituted heteroaryl. The starting material of each method is commercially available or can be synthesized by well-know method from the compound which is commercially available.

[0134] Method A: Synthetic method of the compound wherein Y is an oxadiazole ring and X is —S—.

[0135] wherein Z is above defined.

[0136] Compound (XIV) in a solvent such as ethanol and benzene is reacted with carbon disulfide and a base such as triethylamine, sodium hydroxide, and potassium carbonate at 0° C. to 100° C., preferably 60° C. to 100° C. for 10 min to 24 h, preferably 2 h to 12 h to give compound (XV-1).

[0137] Method B: Synthetic method of the compound wherein Y is an oxadiazole ring and X is —O—.

[0138] wherein Z is above defined.

[0139] To a solution of compound (XIV) in a solvent such as tetrahydrofuran and toluene, is added carbonyldiimidazole, and the mixture is reacted at 0° C. to 120° C., preferably 60° C. to 120° C. for 10 min to 24 h, preferably 2 h to 12 h to give compound (XV-2).

[0140] Method C: Synthetic method of the compound wherein Y is an oxadiazole ring and X is —N(R⁷)—.

[0141] wherein Z is as defined above and R⁷ is as defined above.

[0142] To a solution of compound (XVI) in a solvent such as ethanol and tetrahydrofuran, is added mercury oxide, and the mixture is reacted at 0° C. to 120° C., preferably 30° C. to 80° C. for 0.5 h to 24 h, preferably 1 h to 24 h to give compound (XV-3).

[0143] Method D: Synthetic method of the compound wherein Y is a thiadiazole ring and X is —S—.

[0144] wherein Z is as defined above.

[0145] To a solution of compound (XIV) in a solvent such as ethanol and tetrahydrofuran are added carbon disulfide and a base such as triethylamine and sodium hydroxide and the mixture is reacted at 0° C. to 100° C., preferably 20° C. to 60° C. for 0.5 h to 24 h, preferably 1 h to 12 h. After the solvent is removed, the residue is reacted with conc. sulfuric acid at −20° C. to 40° C., preferably 0° C. to 20° C. for 1 min to 12 h, preferably 10 min to 1 h to give compound (XV-4).

[0146] Method E : Synthetic method of the compound wherein Y is a furan ring and X is −S—.

[0147] wherein Z is as defined above.

[0148] (Step 1)

[0149] Halogenated furan such as 2-bromofuran is reacted with compound (XVII) in a solvent such as N,N-dimethylformamide, toluene, xylene, benzene, tetrahydrofuran, and ethanol in the presence of palladium catalyst such as Pd(Ph₃P)₄ and a base such as potassium carbonate, calcium carbonate, triethylamine, and sodium methoxide to give the aimed compound (XVIII) (Suzuki reaction). The reaction temperature is room temperature to 100° C., preferably room temperature to 80° C. and the reaction time is 5 to 50 h, preferably 15 to 30 h.

[0150] (Step 2)

[0151] To a solution of compound (XVIII) in a solvent such as tetrahydrofuran, diethyl ether, and toluene is added a base such as n-butyllithium and sec-butyllithium, and the mixture is stirred at −100° C. to 50° C., preferably −80° C. to 0° C. for 1 min to 24 h, preferably 10 min to 60 min. To the mixture is added sulfur, and the resulting mixture is reacted at −100° C. to 50° C., preferably −80° C. to 0° C. for 1 h to 24 h, preferably 1 h to 12 h to give the aimed compound (XV-5).

[0152] Method F: Synthetic method of the compound wherein Y is a thiophene ring and X is —S—.

[0153] wherein Z is as defined above and Hal is halogen.

[0154] The steps 1 and 2 can be carried out in a manner similar to those described in step 1 and 2 of Method E.

[0155] Method G: Synthetic method of the compound wherein Y is an oxazole ring and X is —S—.

[0156] wherein Z is as defined above.

[0157] To a solution of compound (XX) in a solvent such as dichloromethane, toluene, and diethyl ether is added thiophosgene in the presence of a base such as triethylamine and sodium hydroxide and the mixture is reacted at −20° C. to 100° C., preferably 0° C. to 40° C. for 1 h to 48 h, preferably 1 h to 24 h to give compound (XV-7).

[0158] Method H: Synthetic method of the compound wherein Y is an oxazole ring and X is —O— or —S—.

[0159] wherein Z is as defined above.

[0160] (Step 1)

[0161] Compound (XXI) in a solvent such as dichloromethane and acetonitrile is reacted with a coupling reagent such as dicyclohexylcarbodiimide at −20° C. to 50° C., preferably 0° C. to 20° C. for 5 min to 24 h, preferably 10 min to 2 h to give compound (XV-8).

[0162] (Step 2)

[0163] To a solution of compound (XV-8) in a solvent such as toluene and dioxane is added Lawesson's reagent, and the mixture is reacted at 60° C. to 150° C., preferably 80° C. to 120° C. for 1 h to 24 h, preferably 2 to 12 h to give compound (XV-9).

[0164] Method I: Synthetic method of the compound wherein Y is an isoxazole ring and X is —O— or —S—.

[0165] wherein Z is as defined above and R¹⁴ is C1 to C3 alkyl.

[0166] (Step 1)

[0167] Compound (XXII) in a solvent such as methanol and tetrahydrofuran is reacted with hydroxylamine at 20° C. to 100° C., preferably 50° C. to 80° C. for 1 h to 24 h, preferably 2 h to 12 h to give compound (XV-10).

[0168] (Step 2)

[0169] Compound (XV-11) can be obtained in a manner similar to that described in step 2 of Method H.

[0170] The compounds which are not concretely shown in the above methods can be synthesized by a combination of the above methods A to I and well-know methods.

[0171] In the methods J to N, R⁵, R⁶, R¹³, Q³, and T³ (wherein R¹, R², R³, and R⁴are as defined above) are as defined above. The starting material of each method is commercially available or can be synthesized by well-know methods from the compound which is commercially available.

[0172] Methods J and K are processes for construction of a pyrimidine ring, and can be carried out in accordance with well-known methods (see Journal of Chemical Society, 1937, p-364, ibid., 1943, p-388 and J. Pharm. Soc. Japan 1954, p-742).

[0173] Methods L to N are processes for introduction a guanidino group to the pyrimidine derivative obtained in the Method J and Method K, and can be carried out in accordance with well-known methods (see Journal of Chemical Society, 1948, p-581, ibid., 1946, p-1063 and Synthesis, 1988, p-460).

[0174] Method J-1: Synthesis of a pyrimidine ring wherein both R^(X) and R^(Y) are hydrogen atom.

[0175] wherein R⁵, R⁶ and R¹³ are as defined above; and R^(X) and R^(Y) are hydrogen atom.

[0176] (Step 1)

[0177] Compound (XXIII) in a solvent such as ethanol, tetrahydrofuran, and N,N-dimethylformamide is reacted with R⁵—C(═S)—NH₂ in the presence of a base such as sodium ethylate and sodium hydroxide at 0° C. to 150° C., preferably 60° C. to 100° C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXIV).

[0178] (Step 2)

[0179] Compound (XXIV) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with a reducing agent such as lithium aluminum hydride and lithium borohydride at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like, to give compound (XXV).

[0180] Method J-2: Synthesis of a pyrimidine ring wherein one of R^(X) and R^(Y) is hydrogen atom.

[0181] wherein R⁵, R⁶ and R¹³ are as defined above; R^(X) is alkyl; and R^(Y) are hydrogen atom or alkyl.

[0182] (Step 1)

[0183] Compound (XXIV) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with a reducing agent such as lithium aluminum hydride and lithium borohydride at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h to give compound (XXVI).

[0184] (Step 2)

[0185] Compound (XXVI) in a solvent such as dichloromethane and chloroform is reacted with a oxidizing agent such as manganese dioxide, pyridinium dichromate, and pyridinium chlorochromate at −20° C. to 100° C., preferably 0° C. to 40° C. for 0.5 h to 14 days, preferably 1 h to 7 days to give an aldehyde derivative. The obtained aldehyde derivative in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as R^(X)MgBr or organometallic reagent such as R^(X)Li at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like, to give compound (XXV).

[0186] Method J-3: Synthesis of a pyrimidine ring wherein both of R^(X) and R^(Y) are not hydrogen atom.

[0187] wherein R⁵, R⁶ and R¹³ are as defined above; R^(X) and R^(Y) are each independently alkyl or alkyloxy; R¹⁵ is alkyl such as methyl and ethyl.

[0188] (Step 1)

[0189] Compound (XXVII) in a solvent such as ethanol, tetrahydrofuran, and N,N-dimethylformamide is reacted with R⁵—C(═N)—NH₂ in the presence of a base such as sodium ethylate and sodium hydroxide, at 0° C. to 150° C., preferably 60° C. to 100° C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXVIII).

[0190] (Step 2)

[0191] Compound (XXVIII) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as R^(X)MgBr or organometallic reagent such as R^(X)Li at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h. To the mixture an acid aqueous solution such as hydrochloric acid and sulfuric acid is added, and then the resulting mixture is stirred at −20° C. to 100° C., preferably 0° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h to give compound (XXIX).

[0192] (Step 3)

[0193] Compound (XXIX) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as R^(X)MgBr or organometallic reagent such as R^(X)Li at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like, to give compound (XXX).

[0194] Method J-4: Synthesis of a pyrimidine ring wherein R^(X) and R^(Y) are same.

[0195] wherein R⁵, R⁶ and R¹³ are as defined above; R^(X) and R^(Y) are same as alkyl or alkyloxy.

[0196] (Step 1)

[0197] Compound (XXIV) in a solvent such as ether and tetrahydrofuran or in a mixed solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as R^(X)MgBr or organometallic reagent such as R^(X)Li at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like to give compound (XXV).

[0198] Method J-5: Synthesis of a pyrimidine ring wherein one of R^(X) and R^(Y) is hydrogen atom.

[0199] wherein R⁵, R⁶ and R¹³ are as defined above; one of R^(X) and R^(Y) is hydrogen atom and the other is hydrogen atom, alkyl or alkyloxy.

[0200] (Step 1)

[0201] Compound (XXVIII) in a solvent such as ether and tetrahydrofuran or a mixed in solvent such as ether-tetrahydrofuran is reacted with Grignard reagent such as R^(X)MgBr or organometallic reagent such as R^(X)Li at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h. To the mixture an acid aqueous solution such as hydrochloric acid and sulfuric acid is added, and then the resulting mixture is stirred at −20° C. to 100° C., preferably 0° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h to give compound (XXIX).

[0202] (Step 2)

[0203] Compound (XXIX) in a solvent such as ether, tetrahydrofuran, methanol, and ethanol or their mixed solvent is reacted with a reducing agent such as sodium borohydride, lithium borohydride, and lithium aluminum hydride at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.5 h to 24 h, preferably 1 h to 12 h to give an alcohol derivative. The obtained alcohol derivative is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) and the like to give compound (XXV).

[0204] Method K: Synthesis of a pyrimidine ring.

[0205] wherein R¹, R⁵, R⁶ and R¹³ are as defined above.

[0206] (Step 1)

[0207] Compound (XXVI) in a solvent such as ethanol, tetrahydrofuran, and N,N-dimethylformamide is reacted with R⁵—C(═NH)—NH₂ or its salt in the presence of a base such as sodium ethylate and sodium hydroxide at 0° C. to 150° C., preferably 60° C. to 100° C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXVII) or its salt.

[0208] (Step 2)

[0209] Compound (XXVII) or its salt in a solvent such as toluene and dichloroethane or without solvent is reacted with a halogenating reagent such as thionyl chloride and phosphorus oxychloride at 0° C. to 150° C., preferably 60° C. to 120° C. for 0.5 h to 12 h, preferably 1 h to 5 h to give a halogenated compound. The obtained halogenated compound in a solvent such as ethanol and tetrahydrofuran is reacted with R¹NH₂ at −80° C. to 100° C., preferably −20° C. to 30° C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XXVIII).

[0210] (Step 3)

[0211] This step can be carried out in a manner similar to that described in step 2 of Method J-1.

[0212] Method L: Introduction of a guanidino group

[0213] wherein R¹, R², R³, R⁴, R⁵, R⁶ and R¹³ are as defined above.

[0214] (Step 1)

[0215] Compound (XXV) in a solvent such as N,N-dimethylformamide, pyridine, and tetrahydrofuran is reacted with R³—NCS or R³R⁴NCS-Hal wherein Hal is halogen, in the presence or absence of a base such as sodium hydride at −20° C. to 120° C., preferably 0° C. to 120° C. for 0.5 h to 48 h, preferably 1 h to 24 h to give compound (XXIX).

[0216] (Step 2)

[0217] To a solution of compound (XXIX) in a solvent such as methanol and tetrahydrofuran are added a heavy metal salt or heavy metal oxide such as HgO and R¹R²NH, and the mixture is reacted at −20° C. to 100° C., preferably 0° C. to 50° C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XII-1).

[0218] Method M: Introduction of a guanidino group

[0219] wherein R¹, R³, R⁴, R⁵, R⁶ and R¹³ are as defined above.

[0220] (Step 1)

[0221] To a solution of compound (XXV) in a solvent such as N,N-dimethylformamide and tetrahydrofuran in the presence of a base such as sodium hydride and potassium butoxide added carbon disulfide and then alkylating reagent such as R¹I and R¹ ₂SO₄, and the mixture is reacted at 0° C. to 100° C., preferably 20° C. to 60° C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XII-2).

[0222] (Step 2)

[0223] Compound (XII-2) in a solvent such as methanol and N,N-dimethylformamide is reacted with R³R⁴NH at 0° C. to 150° C., preferably 0° C. to 100° C. for 0.5 h to 48 h, preferably 1 h to 12 h to give compound (XII-3).

[0224] (Step 3)

[0225] Compound (XII-3) in a solvent such as methanol and N,N-dimethylformamide is reacted with R¹R²NH at 20° C. to 150° C., preferably 40° C. to 80° C. for 0.5 h to 48 h, preferably 4 h to 24 h to give compound (XII-4).

[0226] Method N: Introduction of a guanidino group wherein R¹ is not hydrogen atom.

[0227] wherein R¹, R², R³, R⁴, R⁵, R⁶ and R¹³ are as defined above.

[0228] (Step 1)

[0229] This step can be carried out in a manner similar to that described in step 1 of Method L.

[0230] (Step 2)

[0231] This step can be carried out in a manner similar to that described in step 2 of Method L.

[0232] When a compound contains a functional group(s) possibly interfering the reaction such as hydroxy, mercapto, and amino group in the each step of Method A to Method N, it can previously be protected and deprotected at an appropriate stage by the method described Protective Groups in Organic Synthesis, Theodora W. Green (John Wiley & Sons).

[0233] The term “the compounds of the present invention” herein used includes pharmaceutically acceptable salts and hydrates of the compounds. For example, salts with alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids (e.g., acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid) are exemplified. These salts can be formed by usual methods. The hydrates may coordinate with an arbitrary number of water molecule.

[0234] The compounds of the present invention is not restricted to any particular isomers but includes all possible isomers and racemate.

[0235] The compounds of the present invention have an inhibitory activity against a signal derived from Ras oncogene products as shown in the experimental examples below.

[0236] Consequently, the compounds of the present invention can be used as a therapeutic agent for cancer, preferably solid tumor such as pancreatic cancer, colon cancer, and lung cancer.

[0237] When the compounds of this invention is administered to a patient for the treatment of the above diseases, they can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, liquid medicine, or the like, or by parenteral administration such as injections, suppository, percutaneous formulations, insufflation, or the like. An effective amount of the compound of this invention is formulated by being mixed with appropriate medicinal admixture such as excipient, binder, penetrant, disintegrators, lubricant, and the like, if necessary. When parenteral injection is prepared, the compound of this invention and an appropriate carrier are sterilized to formulate.

[0238] An appropriate dosage varies with the conditions of the patients, an administration route, their age, and their body weight. In the case of oral administration to an adult, the dosage can generally be between 0.01-100 mg/kg/day, preferably 0.1-20 mg/kg/day.

[0239] The following examples are provided to further illustrate the present invention and are not to be construed as limiting the scope thereof.

[0240] In the examples, the following abbreviations are used.

[0241] Me: methyl

[0242] Et: ethyl

[0243] Pr: n-propyl

[0244] i-Pr: isopropyl

[0245] Bu: n-butyl

[0246] DMF: dimethylformamide

[0247] THF: tetrahydrofuran

[0248] DMSO: dimethylsulfoxide

[0249] TBS: tert-butyldimethylsilyl

[0250] TBDPS; tert-butyldiphenylsilyl

[0251] In ¹H-NMR, the value of δ is represented by ppm, s is singlet, d is doublet, t is triplet, q is quartet, quit is quintet, sext is sextet, and br is broad. The value of J is represented by Hz.

EXAMPLE Example 1

[0252]

[0253] Step 1

[0254] To a solution of potassium t-butoxide (8.05 g) in 60 ml of DMF was added dropwise a solution of compound 1 (10.0 g) which was obtained by well-known method (M. Tomita, S. Uyeo, A. Takamizawa and R. Maeda, Yakugakuzasshi, 74, 742 (1954)), in 29 ml of DMF with stirring at ice-cooling. The reaction mixture was allowed to room temperature and stirred for 1 h. To the resulting mixture was added a solution of methylisothiocyanate (5.25 g) in 7.5 ml of DMF at ice-cooling and stirred for 2 h at room temperature. After confirming the disappearance of compound 1, a solution of methyl iodide (12.7 g) in 1.5 ml of DMF was added to the mixture at ice-cooling. The mixture was stirred for 1 h at room temperature and DMF was removed under reduced pressure, and then water was added to the residue. The mixture was extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8.15 g of compound 2.

[0255]¹H-NMR (CDCl₃): 1.26 (3H, t, J=6.9 Hz), 2.52 (3H, s), 2.56 (3H, s), 3.07 (3H, d, J=5.3 Hz), 3.60 (2H, q, J=6.9 Hz), 4.61 (2H, s), 8.41 (1H, s).

[0256] Step 2

[0257] A solution of compound 2 (2.50 g) in 25 ml of 25% hydrobromic acid/acetic acid was reacted for 7 h at 70° C. The solvent was removed under reduced pressure, and the residue was dissolved in 10 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (2.41 g) which was obtained in similar to described (R. W. Young and K. H. Wood. J. Am. Chem. Soc., 77, 400 (1955)) and potassium carbonate (5.43 g) in 25 ml of DMF. The reaction mixture was stirred for 1 h at room temperature and added water. The appeared crystal was filtered to give 2.56 g of compound A-1. The physical data was shown in Table 1.

Example 2 to 17

[0258] Compounds A-2 to A-17 were synthesized in a manner similar to described in Example 1. The physical data were shown in Tables 1 to 2.

Example 18

[0259]

[0260] Step 1

[0261] To a solution of potassium t-butoxide (3.43 g) in 30 ml of DMF was added dropwise a solution of compound 1 (4.64 g) in 12 ml of DMF with stirring at ice-cooling. The reaction mixture was allowed to room temperature and stirred for 30 min. To the resulting mixture was added dropwise a solution of propylisothiocyanate (3.09 g) in 3 ml of DMF at ice-cooling and stirred for 1.5 h at room temperature. After confirming the disappearance of compound 1, a solution of methyl iodide (5.91 g) in 3 ml of DMF was added to the mixture at ice-cooling. The mixture was stirred for 1 h at room temperature. DMF was removed under reduced pressure and added water. The resulting mixture was extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added hexane, the appeared crystal was filtered to give 2.25 g of compound 3.

[0262]¹H-NMR (CDCl₃): 1.06 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz), 1.71 (2H, sext, J=7.3 Hz), 2.51 (3H, s), 2.55 (3H, s), 3.35 (2H, q, J=7.3 Hz), 3.60 (2H, q, J=7.3 Hz), 4.61 (2H, s), 8.41 (1H, s), 11.31 (1H, br).

[0263] Step 2

[0264] A solution of compound 3 (0.10 g) and dimethylhydrazine (0.43 g) in 2 ml of ethanol was stirred for 3 days at 65° C. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 0.03 g of compound 4.

[0265]¹H-NMR (CDCl₃): 0.96 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.62 (2H, sext, J=7.3 Hz), 2.50 (3H, s), 2.61 (6H, s), 3.37 (2H, q, J=7.3 Hz), 3.60 (2H, q, J=7.3 Hz), 4.53 (2H, s), 6.25 (1H, br), 8.21 (1H, s), 10.94 (1H, br).

[0266] Step 3

[0267] A solution of compound 4 (0.03 g) in 0.3 ml of 25% hydrobromic acid in acetic acid was reacted for 7 h at 70° C. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (0.03 g) and potassium carbonate (0.06 g) in 2 ml of DMF. The reaction mixture was stirred for 1 h at ice-cooling and added water. The appeared crystal was filtered and recrystalized from ethyl acetate/hexane to give 0.02 g of compound A-18. The physical data were shown in Table 2.

Example 19

[0268] Compounds A-19 was synthesized in a manner similar to described in Example 18. The physical data were shown in Table 3.

Example 20

[0269]

[0270] Step 1

[0271] To a solution of potassium t-butoxide (0.73 g) in 15 ml of DMF was added dropwise a solution of compound 1 (1.00 g) in 5 ml of DMF with stirring at ice-cooling. To the resulting mixture was added dropwise 3-t-butyldiphenylsilyloxypropylisothiocyanate (2.33 g) which was obtained easily from 3-amino-1-propanol by usual method and stirred for 17 h. To the reaction mixture was added water, and the mixture was extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.10 g of compound 5.

[0272]¹H-NMR (CDCl₃): 1.05 (9H, s), 1.36 (3H, t, J=6.9 Hz), 1.98 (2H, quint, J=6.6 Hz), 2.42 (3H, s), 3.63 (2H, q, J=6.9 Hz), 3.81 (2H, t, J=6.6 Hz), 3.89 (2H, q, J=6.6 Hz), 4.51 (2H, s), 7.31-7.41 (6H, m), 7.64-7.68 (4H, m), 8.22 (1H, s), 9.40 (1H, br), 11.48 (1H, br).

[0273] Step 2

[0274] A solution of compound 5 (1.00 g) and p-toluenesulfonic acid monohydrate (0.76 g) in 5 ml of toluene was heated with stirring for 2 h under reflux. To the resulting mixture were added water and saturated sodium hygrogencarbonate aqueous solution. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of compound 6.

[0275]¹H-NMR (CDCl₃): 1.26 (3H, t, J=6.9 Hz), 2.13-2.21 (2H, m), 2.54 (3H, s), 3.07-3.12 (2H, m), 3.55-3.62 (2H, m), 3.61 (2H, q, J=6.9 Hz), 4.57 (2H, s), 8.38 (1H, s), 11.81 (1H, br).

[0276] Step 3

[0277] A solution of compound 6 (0.10 g) in 0.8 ml of 25% hydrobromic acid/acetic acid was reacted for 14 h at 70° C. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (0.09 g) and potassium carbonate (0.21 g) in 2 ml of DMF at ice-cooling. The reaction mixture was stirred for 1 h at ice-cooling and added water. The appeared crystal was filtered and recrystalized from dichloromethane/diethyl ether/hexane to give 0.07 g of compound A-20. The physical data were shown in Table 3.

Example 21

[0278] Compounds A-21 was synthesized in a manner similar to described in Example 20. The physical data were shown in Table 3.

Example 22

[0279]

[0280] Step 1

[0281] To a suspension of lithium aluminum hydride (4.4 g) in 220 ml of THF was added dropwise a solution of 4-amino-5-ethoxycarbonyl-2-methylpyrimidine 7 (22.0 g) which was obtained by the method described in literature (G. W. Kenner, B. Lythgoe, A. R. Todd and A. Topham. J. Chem. Soc., 388 (1943)) in 220 ml of THF with stirring at ice-cooling. The reaction mixture was allowed to room temperature and stirred for 2 h. To the mixture was added excess of ice and the stirring was continued for additional 2 h. To the reaction mixture was added anhydrous sodium sulfate, and the stirring was continued. The THF-insoluble material was filterd off and washed with methanol. The combined filtrate was concentrated completely under reduced pressure and added ethanol. The ethanol solution was heated and the insoluble material was filtered off. The ethanol-soluble filtrate was cooled and the appeared insoluble material was filtered off again. The filtrate was diluted with diethyl ether and the appeared crystals were filterd to give 14.5 g of compound 8.

[0282] Melting Point :191˜192° C.,

[0283]¹H-NMR (DMSO-d₆) 2.28 (3H, s), 4.30 (2H, s), 7.90 (1H, s).

[0284] Step 2

[0285] To a solution of compound 8 (500 mg) in a combined solvent of 10 ml of dichloromethane and 5 ml of methanol was added active manganese dioxide (2.5 g), and stirred for 6 days at room temperature. The dichloromethane-insoluble material was filtered off and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography and crystalized from diethyl ether to give 284 mg of compound 9.

[0286]¹H-NMR (CDCl₃): 2.58 (3H, s), 5.84 (1H, br), 8.13 (1H, br), 8.57 (1H, s), 9.86 (1H, s).

[0287] Step 3

[0288] A solution of compound 9 (280 mg) in 14 ml of THF was heated to dissolve and the mixture was allowed to ice-cooling. To the mixture was added dropwise 0.93 M solution of methylmagnesium bromide in THF (8.8 ml) with stirring at ice-cooling. The reaction mixture was stirred for 20 min at room temperature. Ice-water was added to the mixture, and the mixture was extracted with ethyl acetate. And the aqueous layer was rextracted with methyl ethyl ketone. The combined organic layer was concentrated under reduced pressure, and 10% solution of metanol in dichloromethane was added to the residue, then the insolble material was filtered off. The filtrate was subjected to silica gel column chromatography and then crystalized from diethyl ether/hexane to give 188 mg of compound 10.

[0289]¹H-NMR (CDCl₃): 1.57 (3H, d, J=6.6 Hz), 2.13 (1H, br), 2.48 (3H, s), 4.86 (1H, q, J=6.6 Hz), 5.55 (2H, br), 7.94 (1H, s).

[0290] Step 4

[0291] A solution of compound 10 (188 mg) and imidazole (100 mg) in 10 ml of DMF was added a solution of t-butyldimethylchlorosilane (200 mg) in 2 ml of DMF with stirring at ice-cooling. The mixture was stirred at room temperatuer for 2 h, and then imidazole (50 mg) and t-butyldimethylchlorosilane (100 mg) were added again to the mixture. The reaction mixture was stirred overnight, and added ethyl acetate. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 285 mg of compound 11.

[0292]¹H-NMR (CDCl₃): 0.01 (3H, s), 0.10 (3H, s), 0.88 (9H, s), 1.46 (3H, d, J=6.6 Hz), 2.48 (3H, s), 4.79 (1H, q, J=6.6 Hz), 5.56 (2H, br), 7.87 (1H, s).

[0293] Step 5

[0294] Potassium t-butoxide (140 mg) was added to a solution of compound 11 (285 mg) in 5.0 ml of DMF with stirring at ice-cooling. After stirring for 5 min, ethylisothiocyanate (0.11 ml) was added dropwise. The resulting mixture was stirred for 10 min at ice-cooling and methyl iodide (0.08 ml) was added, and stirred for additional 1 h. To the reaction mixture was added water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 176 mg of compound 12.

[0295]¹H-NMR (CDCl₃): −0.01 (3H, s), 0.05 (3H, s), 0.90 (9H, s), 1.33 (3H, t, J=7.3 Hz), 1.40 (3H, d, J=6.3 Hz), 2.48 (3H, s), 2.55 (3H, s), 3.42 (2H, dq, J=5.6 Hz, 7.3 Hz), 5.36 (1H, q, J=6.3 Hz), 8.54 (1H, s), 11.18 (1H, br).

[0296] Step 6

[0297] A solution of compound 12 (50 m g) in 1.0 ml of 25% hydrobromic acid/acetic acid was reacted for 15 h at 40° C. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (50 mg) and potassium carbonate (105 mg) in 2 ml of DMF at ice-cooling. The reaction mixture was stirried for 1 h at ice-cooling and added water. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and crystalized from diethyl ether to give 16.8 mg of compound A-22. The physical data were shown in Table 3.

Example 23

[0298]

[0299] Step 1

[0300] To a solution of compound 12 (120 mg) in 3.0 ml of ethanol was added 70% ethylamine aqueous solution (0.27 ml), and the mixture was stirred for 5 h at 60° C. An additional 70% ethylamine aqueous solution (0.54 ml) was added to the reaction mixture, stirred overnight at 80° C. After cooling, the solvent was removed under reduced pressure to give 114 mg of compound 13.

[0301]¹H-NMR (CDCl₃): −0.00 (3H, s), 0.04 (3H, s), 0.91 (9H, s), 1.28 (6H, t, J=7.2 Hz), 1.39 (3H, d, J=6.2 Hz), 2.48 (3H, s), 3.33 (4H, br), 5.27 (1H, q, J=6.2 Hz), 8.35 (1H, s).

[0302] Step 2

[0303] A solution of compound 13 (50 m g) in 1.0 ml of 25% hydrobromic acid/acetic acid was reacted for 15 h at 40° C. The solvent was removed under reduced pressure, and the residue was dissolved in 1 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (50 mg) and potassium carbonate (105 mg) in 2 ml of DMF at ice-cooling. The reaction mixture was stirred for 3 h at ice-cooling and added water. The mixture was extracted with dichloromethane and successively with 20% 2-propanol/dichlorometane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and crystalized from methanol to give 24.9 mg of compound A-23. The physical data were shown in Table 3.

Example 24

[0304]

[0305] Step 1

[0306] To a solution of compound A-1 (100 mg) in a mxed solvent of dichoromethane (5.0 ml) and methanol(5.0 ml) was added silver(I) oxide (70 mg), and the reaction mixture was stirred for 4 h at room temperature. The dicholomethane-insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and recrystalized from diethyl ether to give 82.9 mg of compound A-24. The physical data were shown in Table 3.

Example 25 to 27

[0307] Compounds A-25 to A-27 were synthesized in a manner similar to described in Example 24. The physical data were shown in Table 3.

Example 28

[0308]

[0309] Step 1

[0310] To a solution of potassium t-butoxide (3.69 g) in 20 ml of DMF was added dropwise a solution of compound 1 (5.00 g) in 32 ml of DMF with stirring at ice-cooling. The reaction mixture was allowed at room temperature and stirred for 30 min. A solution of ethylisocyanate (2.34 g) in 6 ml of DMF was added dropwise to the mixture at ice-cooling, and the mixture was stirred for 1.5 h at room temperature. After removal of DMF under reduced pressure, water was added to the residure. The mixture was extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6.27 g of compound 14.

[0311]¹H-NMR (CDCl₃): 1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz), 2.60 (3H, s), 3.43 (2H, dq, J=5.6 Hz, 7.3 Hz), 3.55 (2H, q, J=7.3 Hz), 4.46 (2H, s), 7.99 (1H, br), 8.17 (1H, s), 9.36 (1H, br).

[0312] Step 2

[0313] A solution of compound 14 (100 m g) in 2.5 ml of 25% hydrobromic acid in acetic acid was reacted for 5 h at 70° C. The solvent was removed under reduced pressure, and the residue was dissolved in 2 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (120 mg) and potassium carbonate (230 mg) in 3 ml of DMF at ice-cooling. The reaction mixture was stirred for 1 h at ice-cooling, then water was added to the reaction mixture. The insolble precipitate was filtered, dried, and subjected to silica gel column chromatography and crystalized from methanol to give 126 mg of compound B-1. The physical data were shown in Table 5.

Example 29 to 31

[0314] Compounds B-2 to B-4 were synthesized in a manner similar to described in Example 28. The physical data were shown in Table 5.

Example 32

[0315]

[0316] Step 1

[0317] A solution of compound 1 (2.24 g) in 30 ml of 25% hydrobromic acid/acetic acid was reacted for 15.5 h at 70° C. The solvent was removed under reduced pressure, and the residue was dissolved in 10 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (3.13 g) and potassium carbonate (7.14 g) in 35 ml of DMF at ice-cooling. The reaction mixture was stirred for 1 h at ice-cooling and added water. The appeared crystal was filtered to give 3.99 g of compound 15.

[0318]¹H-NMR (DMSO-d₆): 2.28 (3H, s), 4.37 (2H, s), 7.09 (2H, br), 7.67 (2H, d, J=8.6 Hz), 7.98 (2H, d, J=8.6 Hz), 8.06 (1H, s).

[0319] Step 2

[0320] To a solution of compound 15 (200 mg) in 10 ml of DMF was added potassium t-butoxide (70 mg) with stirring at colling with dryice/acetonitrile bath. The reaction mixture was stirred for 5 min and ethylisothiocyanate (0.06 ml) was added to the resulting mixture. The reaction mixture was stirred for 3 min and added acetic acid (0.05 ml). To the reaction mixture was added water at room temperature, extracted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and crystalized from diethyl ether to give 16.3 mg of compound B-5. The physical data were shown in Table 5.

Example 33

[0321]

[0322] Step 1

[0323] To a solution of compound 15 (200 mg) in 10 ml of DMF were added potassium t-butoxide (140 mg) and carbon disulfide (0.04 ml) with stirring at cooling with dryice/acetonitrile bath. After stirring for 5 min, ethyl iodide (0.1 ml) was added. The reaction mixture was stirred for additional 15 min and water was added at room temperature. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give a mixture of compounds B-6, B-7, and A-28.

[0324] Crystals, which were appeared by addition of diethyl ether to obtaind mixture was filtered to give 4.7 mg of compound B-6. The physical data was shown in Table 5.

[0325] The filtrate was subjected again to silica gel column chromatography to separate compounds B-7 and A-28, and then independently crystalized from diethyl ether/hexane to give 2.2 mg of B-7 and 6.1 mg of A-28, respectively. The physical data of compound B-7 and A-26 were shown in Table 5 and Table 3, respectively.

Example 34 to 40

[0326] Compounds A-29 to A-35 were synthesized in a manner similar to described above. The physical data were shown in Table 4.

Example 41

[0327]

[0328] Step 1

[0329] To a suspension of sodium hydride (2.28 g) in 50 ml of DMF was added dropwise a solution of compound 19 (5.56 g) which was obtained by the method described in WO00/04014, and carbon disulfide (3.59 g) in 60 ml of DMF with stirring at ice-cooling. The reaction mixture was allowed to room temperature and stirred for 20 min, and a solution of methyl iodide (9.34 g) in 10 ml of DMF was added dropwise to the mixture at ice-cooling. The resulting mixture was stirred for 1.5 h at room temperature, and DMF was removed under reduced pressure. After addition of water the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4.45 g of compound 20.

[0330]¹H-NMR (CDCl₃): 0.10 (6H, s), 0.94 (9H, s), 2.54 (6H, s), 2.67 (3H, s), 4.64 (2H, s), 8.63 (1H, s).

[0331] Step 2

[0332] A solution of compound 20 (0.06 g) and 3-amino-1-propanol (0.02 g) in 1 ml of methanol was stirred for 16 h at 30° C. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 0.06 g of compound 21.

[0333]¹H-NMR (CDCl₃): 0.10 (6H, s), 0.95 (9H, s), 1.94 (2H, quint, J=6.6 Hz), 2.48 (3H, s), 2.55 (3H, s), 3.54 (2H, q, J=6.6 Hz), 3.83 (2H, t, J=6.6 Hz), 4.83 (2H, s), 8.48 (1H, s), 11.22 (1H, br).

[0334] Step 3

[0335] To a solution of compound 21 (0.06 g) in 0.5 ml of THF was added potassium t-butoxide (0.02 g) with stirring at room temperature, and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 0.05 g of compound 22.

[0336]¹H-NMR (CDCl₃): 0.10 (6H, s), 0.94 (9H, s), 2.11 (2H, quint, J=5.3 Hz), 2.55 (3H, s), 3.58 (2H, t, J=5.3 Hz), 4.40 (2H, t, J=5.3 Hz), 4.79 (2H, s), 8.45 (1H, s), 11.38 (1H, br).

[0337] Step 4

[0338] A solution of compound 22 (0.04 g) and tetrabutylammonium fluoride trihydrate (0.04 g) in 1 ml of THF was stirried for 18 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 0.02 g of crude compound 23. This crude compound 23 was used for Step 5 without purification.

[0339] Step 5

[0340] To a solution of the crude compound 22 (0.02 g) which was obtained at Step 4 in 1 ml of 1,2-dichloroethane were added thionyl chloride (0.01 g) and catalytic amount of DMF with stirring at room temperature. The mixture was stirred for 1 h at room temperature and for 10 min at 80° C. The solvent was removed under reduced pressure and the residue was dissolved in 1 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (0.02 g) which was obtained by similar method described in a literature (R. W. Young and K. H. Wood. J. Am. Chem. Soc., 77, 400 (1955)) and potassium carbonate (0.06 g) in 1 ml of DMF. The reaction mixture was stirred for 1 h at room temperature and added water. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and crystalized from methanol/diethyl ether/hexane to give 0.02 g of compound B-8. The physical data were shown in Table 5.

Example 42

[0341]

[0342] Step 1

[0343] A solution of compound 17 (0.95 g), which was obtained by similar method described in reference example 1, in 13 ml of 7N ammonia in methanol was reacted for 4 days at 80° C. in sealed tube. The solvent was removed under reduced pressure and added dichloromethane. The insoluble material was filtered to give 0.21 g of compound 24. The filtrate was cocentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 0.39 g of compound 25.

[0344] Compound 24

[0345]¹H-NMR (CDCl₃): 1.27 (3H, t, J=7.3), 2.54 (3H, s), 3.60 (2H, q, J=7.3 Hz), 4.09 (2H, q-like, J=8.9 Hz), 4.54 (2H, s), 8.34 (1H, s).

[0346] Compound 25

[0347]¹H-NMR (CDCl₃): 1.27 (3H, t, J=7.3), 2.58 (3H, s), 3.61 (2H, q, J=7.3 Hz), 3.94 (3H, s), 3.91-3.98 (2H, m), 4.59 (2H, s), 8.44 (1H, s), 10.73 (1H, br).

[0348] Step 2

[0349] A solution of compound 25 (0.10 g) in 1.0 ml of 25% hydrobromic acid/acetic acid was reacted for 7 h at 70° C. The solvent was removed under reduced pressure, and the residue was dissolved in 1.5 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (0.08 g) and potassium carbonate (0.18 g) in 1 ml of DMF at ice-cooling. The reaction mixture was stirred for 1 h at ice-cooling and added water. The appeared crystal was filtered and crystalized from methanol/dichloromethane/diethyl ether to give 0.06 g of compound B-9. The physical data were shown in Table 5.

[0350] Reference

[0351] Reference 1

[0352] Step 1

[0353] To a solution of compound 1 (6.00 g) in 40 ml of DMF was added carbon disulfide (6.00 g) and the mixture was added dropwise to a solution of potassium t-butoxide (10.5 g) in 50 ml of DMF at ice-cooling. The reaction mixture was allowed to room temperature and stirred for 1.5 h, and then a solution of methyl iodide (15.3 g) in 10 ml of DMF was added at ice-cooling. The mixture was stirred for 1.5 h at room temperature, and then DMF was removed under reduced pressure and added water. The resulting mixture was extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3.05 g of compound 16.

[0354]¹H-NMR (CDCl₃): 1.24 (3H, t, J=7.0 Hz), 2.55 (6H, s), 2.67 (3H, s), 3.55 (2H, q, J=7.0 Hz), 4.43 (2H, s), 8.41 (1H, s).

[0355] Step 2

[0356] To a suspension of compound 16 (3.05 g) and 2,2,2-trifluoroethylamine hydrochloride (6.09 g) in 30 ml of DMF was added triethylamine (4.55 g) and the mixture was stirred for 4days at 50° C. To the mixture was added water, and then mixture was extracted with diethyl ether, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.62 g of compound 17.

[0357]¹H-NMR (CDCl₃): 1.27 (3H, t, J=7.3 Hz), 2.55 (3H, s), 2.58 (3H, s), 3.60 (2H, q, J=7.3 Hz), 4.03 (2H, dq, J=8.6 Hz, 6.3 Hz), 4.62 (2H, s), 8.50 (1H, s).

[0358] Step 3

[0359] A solution of compound 17 (2.62 g) and 40% methylamine in methanol (50 ml) in 15 ml of DMF was stirred for 2 days at 60° C. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to give 2.10 g of compound 18.

[0360]¹H-NMR (CDCl₃): 1.26 (3H, t, J-7.1 Hz), 2.52 (3H, s), 2.98 (3H, d, J=5.1 Hz), 3.60 (2H, q, J=7.1 Hz), 4.20 (2H, dq, J=8.9 Hz, 6.4 Hz), 4.52 (2H, s), 8.29 (1H, s).

[0361] Step 4

[0362] A solution of compound 18 (2.10 g) in 20 ml of 25% hydrobromic acid in acetic acid was reacted for 7 h at 70° C. The solvent was removed under reduced pressure, and the residue was dissolved in 15 ml of DMF. The resulting mixture was added to a suspension of 2-(4-nitrophenyl)-5-mercapto-1,3,4-oxadiazole (1.69 g) and potassium carbonate (3.80 g) in 15 ml of DMF at ice-cooling. The reaction mixture was stirred for 1 h at room temperature and added water. The appeared precipitate was filtered, dried, and subjected to silica gel column chromatography and crystalized from methanol/dichloromethane/diethyl ether to give 3.24 g of compound C-1. The physical data was shown in Table 6.

[0363] Reference 2

[0364] Step 1

[0365] To a compound A-1 (4.00 g) were added DMF (200 ml) and propargylamine (7.66 g), and the mixture was stirred for 17 h at 65° C. DMF was removed under reduced pressure and water and brine were added. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and crystalized from methanol/dichloromethane/diethyl ether to give 0.74 g of compound C-2. The physical data were shown in Table 6. TABLE 1

Example Compound ¹H-NMR(CDCl₃) No. No. R¹⁸ R^(X) R¹⁵ R¹⁶ (δ)ppm 1 A-1 NO₂ H SMe NHMe 2.56(3H, s), 2.57(3H, s), 3.10(3H, d, J= 5.3), 4.58(2H, s), 8.16(2H, d, J=9.1), 8.35(2H, d, J=9.1), 8.53(1H, s), 11.18(1H, br) 2 A-2 NO₂ H SMe NH₂ 2.57(3H, s), 2.58(3H, s), 4.60(2H, s), 8.17(2H, d, J=9.1), 8.36(2H, d, J=9.1), 8.61(1H, s) 3 A-3 NO₂ H SMe NHEt 1.35(3H, t, J=7.3), 2.55(3H, s), 2.57(3H, s), 3.45(2H, dq, J=7.3, 5.3), 4.58(2H, s), 8.16(2H, d, J=8.7), 8.36(2H, d, J=8.7), 8.53(1H, s), 11.31(1H, br) 4 A-4 NO₂ H SMe NHPr 1.07(3H, t, J=7.3), 1.73(2H, sext, J=7.3), 2.55(3H, s), 2.57(3H, s), 3.38(2H, q, J= 7.3), 4.58(2H, s), 8.16(2H, d, J=9.1), 8.35(2H, d, J=9.1), 8.53(1H, s), 11.44(1H, br) 5 A-5 NO₂ H SEt NHMe 1.41(3H, t, J=7.3), 2.55(3H, s), 3.09(3H, d, J=5.1), 3.22(2H, q, J=7.3), 4.57(2H, s), 8.17(2H, d, J=9.1), 8.35(2H, d, J=9.1), 8.53(1H, s), 11.23(2H, br) 6 A-6 NO₂ H SEt NHEt 1.34(3H, t, J=7.3), 1.41(3H, t, J=7.3), 2.51(3H, s), 3.21(2H, q, J=7.3), 3.44(2H, dq, J=7.3, 5.3), 4.57(2H, s), 8.17(2H, d, J= 9.1), 8.35(2H, d, J=9.1), 8.53(1H, s), 11.39(1H, br) 7 A-7 NO₂ H SPr NHMe 1.05(3H, t, J=7.3), 1.80(2H, sext, J=7.3), 2.55(3H, s), 3.10(3H, d, J=5.1), 3.19(2H, t, J=7.3), 4.56(2H, s), 8.17(2H, d, J=9.1), 8.35(2H, d, J=9.1), 8.53(1H, s), 11.26(1H, br) 8 A-8 NO₂ H SPr NHEt 1.05(3H, t, J=7.3), 1.34(3H, t, J=7.3), 1.79(2H, sext, J=7.3), 2.54(3H, s), 3.18(2H, t, J=7.3), 3.45(2H, dq, J=7.3, 5.4), 4.56(2H, s), 8.17(2H, d, J=9.1), 8.35(2H, d, J=9.1), 8.53(1H, s), 11.38(1H, br) 9 A-9 NH₂ H SMe NH₂ 2.56(3H, s), 2.58(3H, s), 4.03(2H, s), 4.53(2H, s), 6.71(2H, d, J=8.7), 7.76(2H, d, J=8.7), 8.58(1H, s)

[0366] TABLE 2 Exam- Com- ple pound ¹H-NMR(CDCl₃) No. No. R¹⁸ R^(x) R¹⁵ R¹⁶ (δ) ppm 10 A-10 NH₂ H SMe NHMe 2.55(3 H, s), 2.56(3 H, s), 3.08(3 H, d, J = 5.3), 4.02(2 H, br), 4.51(2 H, s), 6.70(2 H, d, J = 8.9), 7.76(2 H, d, J = 8.9), 8.49(1 H, s), 11.13(1 H, br) 11 A-11 NH₂ H SMe NHEt 1.34(3 H, t, J = 7.3), 2.54(3 H, s), 2.56(3 H, s), 3.43(2 H, dq, J = 7.3, 5.4), 3.50(2 H, br), 4.01(2 H, s), 6.71(2 H, d, J = 8.7), 7.76(2 H, d, J = 8.7), 8.49(1 H, s), 11.30(1 H, br) 12 A-12 NH₂ H SMe NHPr 1.06(3 H, t, J = 7.3), 1.72(2 H, sext, J = 7.3), 2.54(3 H, s), 2.56(3 H, s), 3.36(2 H, q, J = 7.3), 4.02(2 H, br), 4.51(2 H, s), 6.71(2 H, d, J = 8.7), 7.76(2 H, d, J = 8.7), 8.49(1 H, s) 13 A-13 NH₂ H SEt NHMe 1.41(3 H, t, J = 7.3), 2.55(3 H, s), 3.08(3 H, d, J = 5.1), 3.21(2 H, q, J = 7.3), 4.02(2 H, br), 4.51(2 H, s), 6.70(2 H, d, J = 8.5), 7.76(2 H, d, J = 8.5), 8.50(1 H, s) 14 A-14 NH₂ H SEt NHEt 1.33(3 H, t, J = 7.3), 1.39(3 H, t, J = 7.3), 2.54(3 H, s), 3.20(2 H, q, J = 7.3), 3.43(2 H, dq, J = 7.3, 5.4), 4.02(2 H, br), 4.50(2 H, s), 6.71(2 H, d, J = 8.9), 7.77(2 H, d, J = 8.9), 8.49(1 H, s), 11.33(1 H, br) 15 A-15 NH₂ H SPr NHMe 1.04(3 H, t, J = 7.3), 1.78(2 H, sext, J = 7.3), 2.54(3 H, s), 3.08(3 H, d, J = 5.3), 3.18(2 H, t, J = 7.3), 4.03(2 H, br), 4.49(2 H, s), 6.70(2 H, d, J = 8.9), 7.76(2 H, d, J = 8.9), 8.49(1 H, s), 11.20(1 H, br) 16 A-16 NH₂ H SPr NHEt 1.04(3 H, t, J = 7.3), 1.33(3 H, t, J = 7.3), 1.78(2 H, sext, J = 7.3), 2.54(3 H, s), 3.18(2 H, t, J = 7.3), 3.44(2 H, dq, J = 7.3, 5.4), 4.01(2 H, br), 4.49(2 H, s), 6.71(2 H, d, J = 8.9), 7.76(2 H, d, J = 8.9), 8.49(1 H, s), 11.35(1 H, br) 17 A-17 Me H SMe NHPr 1.06(3 H, t, J = 7.3), 1.72(2 H, sext, J = 7.3), 2.41(3 H, s), 2.54(3 H, s), 2.56(3 H, s), 3.37(2 H, dt, J = 5.4, 7.3), 4.54(2 H, s), 7.28(2 H, d, J = 8.2), 7.86(2 H, d, J = 8.2), 8.51(1 H, s) 18 A-18 NO₂ H NHNMe₂ NHPr 1.00(3 H, t, J = 7.3), 1.67(2 H, sext, J = 7.3), 2.51(3 H, s), 2.64(6 H, s), 3.44(2 H, q, J = 7.3), 4.52(2 H, s), 6.39(1 H, br), 8.18(2 H, d, J = 9.0), 8.34(1 H, s), 8.36(2 H, d, J = 9.0)

[0367] TABLE 3 Exam- Com- ple pound ¹H-NMR(CDCl₃) No. No. R¹⁸ R^(x) R¹⁵ R¹⁶ (δ) ppm 19 A-19 NO₂ H NHOMe NHMe 2.52(1.95 H, s), 2.58(1.05 H, s), 2.83(1.05 H, d, J = 5.1), 3.05(1.95 H, d, J = 5.1), 3.75(1.05 H, s), 3.81(1.95 H, s), 4.49(0.7 H, s), 4.53(1.3 H, s), 5.62(0.65 H, br), 7.77(0.35 H, br), 8.16(2 H, d, J = 8.5), 8.35(2 H, d, J = 8.5), 8.36(1 H, s) 20 A-20 NO₂ H S(CH₂)₃NH 2.13-2.25(2 H, m), 2.53(3 H, s), 3.08- 3.13(2 H, m), 3.55-3.65(2 H, m), 4.50(2 H, s), 8.16(2 H, d, J = 8.9), 8.35(2 H, d, J = 8.9), 8.49(1 H, s), 11.85(1 H, br) 21 A-21 NO₂ H S(CH₂)₂NH 2.59(3 H, s), 3.31(2 H, t, J = 7.3), 3.92(2 H, br), 4.53(2 H, s), 8.16(2 H, d, J = 8.9), 8.35(2 H, d, J = 8.9), 8.55(1 H, s) 22 A-22 NO₂ Me SMe NHEt 1.34(3 H, t, J = 7.2), 1.95(3 H, d, J = 7.2), 2.56(3 H, s), 2.57(3 H, s), 3.44(2 H, dq, J = 5.4, 7.2), 5.49(1 H, q, J = 7.2), 8.16(2 H, d, J = 8.8), 8.35(2 H, d, J = 8.8), 8.46(1 H, s), 11.36(1 H, br) 23 A-23 NO₂ Me NHEt NHEt 1.29(6 H, t, J = 7.1), 1.95(3 H, d, J = 7.1), 2.48(3 H, s), 3.39(4 H, br), 5.33(1 H, q, J = 7.1), 8.17(2 H, d, J = 9.0), 8.25(1 H, s), 8.34(2 H, d, J = 9.0) 24 A-24 NO₂ H OMe NHMe 2.56(3 H, s), 2.99(3 H, d, J = 5.1), 3.98(3 H, s), 4.55(2 H, s), 8.16(2 H, d, J = 9.2), 8.41(2 H, d, J = 9.2), 8.47(1 H, s), 9.96(1 H, br) 25 A-25 NO₂ H OEt NHMe 1.40(3 H, t, J = 7.2), 2.55(3 H, s), 2.98(3 H, d, J = 4.9), 4.45(2 H, q, J = 7.2), 4.53(2 H, s), 8.16(2 H, d, J = 9.0), 8.35(2 H, d, J = 9.0), 8.45(1 H, s), 10.01(1 H, br) 26 A-26 Me H OMe NHPr 1.02(3 H, t, J = 7.3), 1.63(2 H, tq, J = 6.8, 7.3), 2.41(3 H, s), 2.54(3 H, s), 3.31(2 H, dt, J = 5.6, 6.8), 3.95(3 H, s), 4.51(2 H, s), 7.28(2 H, d, J = 8.3), 7.86(2 H, d, J = 8.3), 8.44(1 H, s), 10.18(1 H, br) 27 A-27 Me H OEt NHPr 1.02(3 H, t, J = 7.3), 1.37(3 H, t, J = 7.1), 1.64(2 H, sext, J = 7.3), 2.41(3 H, s), 2.54(3 H, s), 3.32(2 H, dt, J = 5.5, 7.3), 4.44(2 H, q, J = 7.1), 4.49(2 H, s), 7.28(2 H, d, J = 8.4), 7.86(2 H, d, J = 8.4), 8.43(1 H, s) 33 A-28 Cl H SEt SEt 1.37(6 H, t, J = 7.4), 2.67(3 H, s), 3.16(4 H, q, J = 7.4), 4.44(2 H, s), 7.47(2 H, d, J = 8.9), 7.92(2 H, d, J = 8.9), 8.67(1 H, s),

[0368] TABLE 4 Exam- Com- ple pound ¹H-NMR(CDCl₃) No. No. R¹⁸ R^(x) R¹⁵ R¹⁶ (δ) ppm 34 A-29 NO₂ H SMe NHC 2.58(3 H, s), 2.61(3 H, s), 4.05(2 H, dq, J = H₂CF₃ 6.4, 8.7), 4.60(2 H, s), 8.16(2 H, d, J = 8.9), 8.35(2 H, d, J = 8.9), 8.63(1 H, s), 12.03(1 H, br). 35 A-30 NH₂ H SMe NHC 2.57(3 H, s), 2.60(3 H, s), 4.02(2 H, br), H₂CF₃ 4.03(2 H, dq, J = 6.5, 8.7), 4.53(2 H, s), 6.71(2 H, d, J = 8.8), 7.76(2 H, d, J = 8.8), 8.59(1 H, s), 12.02(1 H, br). 36 A-31 NO₂ H SMe NHPh 2.54(3 H, s), 2.59(3 H, s), 4.64(2 H, s), 7.34(1 H, t, J = 7.6), 7.35(2 H, d, J = 7.6), 7.44(2 H, t, J = 7.6), 8.17(2 H, d, J = 9.2), 8.36(2 H, d, J = 9.2), 8.63(1 H, s), 13.11(1 H, br). 37 A-32 NO₂ H OMe NHEt 1.26(3 H, t, J = 7.3), 2.55(3 H, s), 3.39(2 H, dq, J = 5.6, 7.3), 3.97(3 H, s), 4.55(2 H, s), 8.16(2 H, d, J = 9.0), 8.35(2 H, d, J = 9.0), 8.46( 1H, s), 10.09(1 H, t-like, J = 5.6). 38 A-33 NO₂ H OEt NHEt 1.27(3 H, t, J = 7.3), 1.39(3 H, t, J = 7.1), 2.55(3 H, s), 3.40(2 H, dq, J = 5.6, 7.3), 4.45(2 H, q, J = 7.1), 4.53(2 H, s), 8.16(2 H, d, J = 9.0), 8.35(2 H, d, J = 9.0), 8.45(1 H, s), 10.14(1 H, t-like, J = 5.6). 39 A-34 NO₂ H O^(i)Pr NHMe 1.38(6 H, d, J = 6.1), 2.55(3 H, s), 2.96(3 H, d, J = 4.9), 4.52(2 H, s), 5.40(1 H, sept, J = 6.1), 8.17(2 H, d, J = 8.9), 8.35(2 H, d, J = 8.9), 8.44(1 H, s), 10.06(1 H, br). 40 A-35 NO₂ H O^(i)Pr NHEt 1.26(3 H, t, J = 7.3), 1.37(6 H, d, J = 6.3), 2.54(3 H, s), 3.38(2 H, dq, J = 5.4, 7.3), 4.52(2 H, s), 5.40(1 H, sept, J = 6.3), 8.17(2 H, d, J = 9.0), 8.35(2 H, d, J = 9.0), 8.44(1 H, s), 10.19(1 H, br).

[0369] TABLE 5

Example Compound ¹H-NMR(CDCl₃) No. No. R¹⁸ R²⁰ R¹⁹ X (δ)ppm 28 B-1 NO₂ H NHEt O 1.28(3H, t, J=7.3), 2.60(3H, s), 3.45(2H, dq, J=5.1, 7.3), 4.60(2H, s), 8.17(2H, d, J=8.8), 8.36(2H, d, J=8.8), 8.54(1H, s), 8.85(1H, br), 9.64(1H, t-like, J=5.1) 29 B-2 Cl H NHEt O 1.27(3H, t, J=7.2), 2.59(3H, s), 3.44(2H, dq, J=5.2, 7.2), 4.57(2H, s), 7.46(2H, d, J=8.5), 7.90(2H, d, J=8.5), 8.52(1H, s), 8.97(1H, br), 9.66(1H, t-like, J=5.2) 30 B-3 NH₂ H NHEt O 1.27(3H, t, J=7.3), 2.59(3H, s), 3.44(2H, dq, J=5.2, 7.3), 4.03(2H, br), 4.49(2H, s), 6.69(2H, d, J=8.5), 7.75(2H, d, J= 8.5), 8.47(1H, s), 8.67(1H, br), 9.59(1H, t-like, J=5.2) 31 B-4 NO₂ H NHPr O 1.03(3H, t, J=7.3), 1.67(2H, sext, J= 7.3), 2.60(3H, s), 3.39(2H, dt, J=5.2, 7.3), 4.62(2H, s), 8.17(2H, d, J=8.8), 8.35(2H, d, J=8.8), 8.57(1H, s), 9.13(1H, br), 9.79(1H, t-like, J=5.2) 32 B-5 Cl H NHEt S 1.29(3H, t, J=7.2), 2.64(3H, s), 3.80(2H, dq, J=5.2, 7.2), 4.43(2H, s), 7.50(2H, d, J=8.7), 7.98(2H, d, J=8.7), 8.14(1H, br), 8.28(1H, s) 33 B-6 Cl H SEt S 1.35(3H, t, J=7.3), 2.62(3H, s), 3.38(2H, q, J=7.3), 4.65(2H, s), 7.49(2H, d, J= 8.7), 8.01(2H, d, J=8.7), 8.27(1H, s) 33 B-7 Cl Et SEt S 1.33(3H, t, J=7.4), 1.45(3H, t, J=7.2), 2.65(3H, s), 3.36(2H, q, J=7.4), 4.02(2H, q, J=7.2), 4.64(2H, s), 7.47(2H, d, J= 8.8), 7.83(2H, d, J=8.8), 8.48(1H, s) 41 B-8 NO₂ H NH(CH₂)₃Cl O 2.11(2H, quint, J=6.3), 2.62(3H, s), 3.62(2H, q, J=6.3), 3.68(2H, t, J=6.3), 4.62(2H, s), 8.17(2H, d, J=8.8), 8.36(2H, d, J=8.8), 9.14(1H, br), 9.91(1H, t, J= 6.1) 42 B-9 NO₂ H NHCH₂CF₃ O 2.62(3H, s), 4.10(2H, dq, J=8.9, 6.3), 4.63(2H, s), 8.18(2H, d, J=8.9), 8.36(2H, d, J=8.9), 8.64(1H, s), 9.48(1H, br), 10.52(1H, t, J=6.3)

[0370] TABLE 6

Reference Compound ¹H-NMR No. No. R²¹ (δ)ppm 1 C-1 CH₂CF₃ 2.41(3H, s), 2.91(3H, d, J=4.6), 4.24(2H, dq, J=9.5, 5.7), 4.46(2H, s), 7.37(1H, br), 8.22(2H, d, J=8.8), 8.28(1H, s), 8.41(2H, d, J=8.8), 10.20(1H, br)(in DMSOd₆) 2 C-2 CH₂C≡CH 2.33(1H, s), 2.51(3H, s), 3.00(3H, d, J=4.9), 4.24(2H, br), 4.54(2H, s), 8.16(2H, d, J=9.1), 8.35(2H, d, J=9.1), 8.38(1H, s)(in CDCl₃)

[0371] Compounds D-1 to D-1700 shown in Tablse 7 to Table 23 are able to synthesize in a manner similar to those described in Example 1 or Example 18, and were compounds E-1 to E-60 shown in Table 24 are able to synthesize in a manner similar to described in Example 20.

[0372] Table 7 to Table 24

TABLE 7 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-1 NH₂ SH H 4-NH₂ D-2 NH₂ SMe H 4-NH₂ D-3 NH₂ SEt H 4-NH₂ D-4 NH₂ S-n-Pr H 4-NH₂ D-5 NH₂ S-i-Pr H 4-NH₂ D-6 NH₂ S-n-Bu H 4-NH₂ D-7 NH₂ S-allyl H 4-NH₂ D-8 NH₂ S-propargyl H 4-NH₂ D-9 NH₂ SCH₂CF₃ H 4-NH₂ D-10 NH₂ SCH₂CH₂F H 4-NH₂ D-11 NHMe SH H 4-NH₂ D-12 NHMe SMe H 4-NH₂ D-13 NHMe SEt H 4-NH₂ D-14 NHMe S-n-Pr H 4-NH₂ D-15 NHMe S-i-Pr H 4-NH₂ D-16 NHMe S-n-Bu H 4-NH₂ D-17 NHMe S-allyl H 4-NH₂ D-18 NHMe S-propargyl H 4-NH₂ D-19 NHMe SCH₂CF₃ H 4-NH₂ D-20 NHMe SCH₂CH₂F H 4-NH₂ D-21 NHEt SH H 4-NH₂ D-22 NHEt SMe H 4-NH₂ D-23 NHEt SEt H 4-NH₂ D-24 NHEt S-n-Pr H 4-NH₂ D-25 NHEt S-i-Pr H 4-NH₂ D-26 NHEt S-n-Bu H 4-NH₂ D-27 NHEt S-allyl H 4-NH₂ D-28 NHEt S-propargyl H 4-NH₂ D-29 NHEt SCH₂CF₃ H 4-NH₂ D-30 NHEt SCH₂CH₂F H 4-NH₂ D-31 NHPr SH H 4-NH₂ D-32 NHPr SMe H 4-NH₂ D-33 NHPr SEt H 4-NH₂ D-34 NHPr S-n-Pr H 4-NH₂ D-35 NHPr S-i-Pr H 4-NH₂ D-36 NHPr S-n-Bu H 4-NH₂ D-37 NHPr S-allyl H 4-NH₂ D-38 NHPr S-propargyl H 4-NH₂ D-39 NHPr SCH₂CF₃ H 4-NH₂ D-40 NHPr SCH₂CH₂F H 4-NH₂ D-41 NH-i-Pr SH H 4-NH₂ D-42 NH-i-Pr SMe H 4-NH₂ D-43 NH-i-Pr SEt H 4-NH₂ D-44 NH-i-Pr S-n-Pr H 4-NH₂ D-45 NH-i-Pr S-i-Pr H 4-NH₂ D-46 NH-i-Pr S-n-Bu H 4-NH₂ D-47 NH-i-Pr S-allyl H 4-NH₂ D-48 NH-i-Pr S-propargyl H 4-NH₂ D-49 NH-i-Pr SCH₂CF₃ H 4-NH₂ D-50 NH-i-Pr SCH₂CH₂F H 4-NH₂ D-51 NH-allyl SH H 4-NH₂ D-52 NH-allyl SMe H 4-NH₂ D-53 NH-allyl SEt H 4-NH₂ D-54 NH-allyl S-n-Pr H 4-NH₂ D-55 NH-allyl S-i-Pr H 4-NH₂ D-56 NH-allyl S-n-Bu H 4-NH₂ D-57 NH-allyl S-allyl H 4-NH₂ D-58 NH-allyl S-propargyl H 4-NH₂ D-59 NH-allyl SCH₂CF₃ H 4-NH₂ D-60 NH-allyl SCH₂CH₂F H 4-NH₂ D-61 NH-propargyl SH H 4-NH₂ D-62 NH-propargyl SMe H 4-NH₂ D-63 NH-propargyl SEt H 4-NH₂ D-64 NH-propargyl S-n-Pr H 4-NH₂ D-65 NH-propargyl S-i-Pr H 4-NH₂ D-66 NH-propargyl S-n-Bu H 4-NH₂ D-67 NH-propargyl S-allyl H 4-NH₂ D-68 NH-propargyl S-propargyl H 4-NH₂ D-69 NH-propargyl SCH₂CF₃ H 4-NH₂ D-70 NH-propargyl SCH₂CH₂F H 4-NH₂ D-71 NHCH₂CF₃ SH H 4-NH₂ D-72 NHCH₂CF₃ SMe H 4-NH₂ D-73 NHCH₂CF₃ SEt H 4-NH₂ D-74 NHCH₂CF₃ S-n-Pr H 4-NH₂ D-75 NHCH₂CF₃ S-i-Pr H 4-NH₂ D-76 NHCH₂CF₃ S-n-Bu H 4-NH₂ D-77 NHCH₂CF₃ S-allyl H 4-NH₂ D-78 NHCH₂CF₃ S-propargyl H 4-NH₂ D-79 NHCH₂CF₃ SCH₂CF₃ H 4-NH₂ D-80 NHCH₂CF₃ SCH₂CH₂F H 4-NH₂ D-81 NHCH₂CH₂F SH H 4-NH₂ D-82 NHCH₂CH₂F SMe H 4-NH₂ D-83 NHCH₂CH₂F SEt H 4-NH₂ D-84 NHCHaCH₂F S-n-Pr H 4-NH₂ D-85 NHCH₂CH₂F S-i-Pr H 4-NH₂ D-86 NHCH₂CH₂F S-n-Bu H 4-NH₂ D-87 NHCH₂CH₂F S-allyl H 4-NH₂ D-88 NHCH₂CH₂F S-propargyl H 4-NH₂ D-89 NHCH₂CH₂F SCH₂CF₃ H 4-NH₂ D-90 NHCH₂CH₂F SCH₂CH₂F H 4-NH₂ D-91 NH-n-Bu SH H 4-NH₂ D-92 NH-n-Bu SMe H 4-NH₂ D-93 NH-n-Bu SEt H 4-NH₂ D-94 NH-n-Bu S-n-Pr H 4-NH₂ D-95 NH-n-Bu S-i-Pr H 4-NH₂ D-96 NH-n-Bu S-n-Bu H 4-NH₂ D-97 NH-n-Bu S-allyl H 4-NH₂ D-98 NH-n-Bu S-propargyl H 4-NH₂ D-99 NH-n-Bu SCH₂CF₃ H 4-NH₂ D-100 NH-n-Bu SCH₂CH₂F H 4-NH₂

[0373] TABLE 8 Com- pound No. R¹⁵ R¹⁸ R¹⁷ R¹⁸ D-101 NH₂ SH H 2-NH₂ D-102 NH₂ SMe H 2-NH₂ D-103 NH₂ SEt H 2-NH₂ D-104 NH₂ S-n-Pr H 2-NH₂ D-105 NH₂ S-i-Pr H 2-NH₂ D-106 NH₂ S-n-Bu H 2-NH₂ D-107 NH₂ S-allyl H 2-NH₂ D-108 NH₂ S-propargyl H 2-NH₂ D-109 NH₂ SCH₂CF₃ H 2-NH₂ D-110 NH₂ SCH₂CH₂F H 2-NH₂ D-111 NHMe SH H 2-NH₂ D-112 NHMe SMe H 2-NH₂ D-113 NHMe SEt H 2-NH₂ D-114 NHMe S-n-Pr H 2-NH₂ D-115 NHMe S-i-Pr H 2-NH₂ D-116 NHMe S-n-Bu H 2-NH₂ D-117 NHMe S-allyl H 2-NH₂ D-118 NHMe S-propargyl H 2-NH₂ D-119 NHMe SCH₂CF₃ H 2-NH₂ D-120 NHMe SCH₂CH₂F H 2-NH₂ D-121 NHEt SH H 2-NH₂ D-122 NHEt SMe H 2-NH₂ D-123 NHEt SEt H 2-NH₂ D-124 NHEt S-n-Pr H 2-NH₂ D-125 NHEt S-i-Pr H 2-NH₂ D-126 NHEt S-n-Bu H 2-NH₂ D-127 NHEt S-allyl H 2-NH₂ D-128 NHEt S-propargyl H 2-NH₂ D-129 NHEt SCH₂CF₃ H 2-NH₂ D-130 NHEt SCH₂CH₂F H 2-NH₂ D-131 NHPr SH H 2-NH₂ D-132 NHPr SMe H 2-NH₂ D-133 NHPr SEt H 2-NH₂ D-134 NHPr S-n-Pr H 2-NH₂ D-135 NHPr S-i-Pr H 2-NH₂ D-136 NHPr S-n-Bu H 2-NH₂ D-137 NHPr S-allyl H 2-NH₂ D-138 NHPr S-propargyl H 2-NH₂ D-139 NHPr SCH₂CF₃ H 2-NH₂ D-140 NHPr SCH₂CH₂F H 2-NH₂ D-141 NH-i-Pr SH H 2-NH₂ D-142 NH-i-Pr SMe H 2-NH₂ D-143 NH-i-Pr SEt H 2-NH₂ D-144 NH-i-Pr S-n-Pr H 2-NH₂ D-145 NH-i-Pr S-i-Pr H 2-NH₂ D-146 NH-i-Pr S-n-Bu H 2-NH₂ D-147 NH-i-Pr S-allyl H 2-NH₂ D-148 NH-i-Pr S-propargyl H 2-NH₂ D-149 NH-i-Pr SCH₂CF₃ H 2-NH₂ D-150 NH-i-Pr SCH₂CH₂F H 2-NH₂ D-151 NH-allyl SH H 2-NH₂ D-152 NH-allyl SMe H 2-NH₂ D-153 NH-allyl SEt H 2-NH₂ D-154 NH-allyl S-n-Pr H 2-NH₂ D-155 NH-allyl S-i-Pr H 2-NH₂ D-156 NH-allyl S-n-Bu H 2-NH₂ D-157 NH-allyl S-allyl H 2-NH₂ D-158 NH-allyl S-propargyl H 2-NH₂ D-159 NH-allyl SCH₂CF₃ H 2-NH₂ D-160 NH-allyl SCH₂CH₂F H 2-NH₂ D-161 NH-propargyl SH H 2-NH₂ D-162 NH-propargyl SMe H 2-NH₂ D-163 NH-propargyl SEt H 2-NH₂ D-164 NH-propargyl S-n-Pr H 2-NH₂ D-165 NH-propargyl S-i-Pr H 2-NH₂ D-166 NH-propargyl S-n-Bu H 2-NH₂ D-167 NH-propargyl S-allyl H 2-NH₂ D-168 NH-propargyl S-propargyl H 2-NH₂ D-169 NH-propargyl SCH₂CF₃ H 2-NH₂ D-170 NH-propargyl SCH₂CH₂F H 2-NH₂ D-171 NHCH₂CF₃ SH H 2-NH₂ D-172 NHCH₂CF₃ SMe H 2-NH₂ D-173 NHCH₂CF₃ SEt H 2-NH₂ D-174 NHCH₂CF₃ S-n-Pr H 2-NH₂ D-175 NHCH₂CF₃ S-i-Pr H 2-NH₂ D-176 NHCH₂CF₃ S-n-Bu H 2-NH₂ D-177 NHCH₂CF₃ S-allyl H 2-NH₂ D-178 NHCH₂CF₃ S-propargyl H 2-NH₂ D-179 NHCH₂CF₃ SCH₂CF₃ H 2-NH₂ D-180 NHCH₂CF₃ SCH₂CH₂F H 2-NH₂ D-181 NHCH₂CH₂F SH H 2-NH₂ D-182 NHCH₂CH₂F SMe H 2-NH₂ D-183 NHCH₂CH₂F SEt H 2-NH₂ D-184 NHCH₂CH₂F S-n-Pr H 2-NH₂ D-185 NHCH₂CH₂F S-i-Pr H 2-NH₂ D-186 NHCH₂CH₂F S-n-Bu H 2-NH₂ D-187 NHCH₂CH₂F S-allyl H 2-NH₂ D-188 NHCH₂CH₂F S-propargyl H 2-NH₂ D-189 NHCH₂CH₂F SCH₂CF₃ H 2-NH₂ D-190 NHCH₂CH₂F SCH₂CH₂F H 2-NH₂ D-191 NH-n-Bu SH H 2-NH₂ D-192 NH-n-Bu SMe H 2-NH₂ D-193 NH-n-Bu SEt H 2-NH₂ D-194 NH-n-Bu S-n-Pr H 2-NH₂ D-195 NH-n-Bu S-i-Pr H 2-NH₂ D-196 NH-n-Bu S-n-Bu H 2-NH₂ D-197 NH-n-Bu S-allyl H 2-NH₂ D-198 NH-n-Bu S-propargyl H 2-NH₂ D-199 NH-n-Bu SCH₂CF₃ H 2-NH₂ D-200 NH-n-Bu SCH₂CH₂F H 2-NH₂

[0374] TABLE 9 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-201 NH₂ SH H 4-Cl D-202 NH₂ SMe H 4-Cl D-203 NH₂ SEt H 4-Cl D-204 NH₂ S-n-Pr H 4-Cl D-205 NH₂ S-i-Pr H 4-Cl D-206 NH₂ S-n-Bu H 4-Cl D-207 NH₂ S-allyl H 4-Cl D-208 NH₂ S-propargyl H 4-Cl D-209 NH₂ SCH₂CF₃ H 4-Cl D-210 NH₂ SCH₂CH₂F H 4-Cl D-211 NHMe SH H 4-Cl D-212 NHMe SMe H 4-Cl D-213 NHMe SEt H 4-Cl D-214 NHMe S-n-Pr H 4-Cl D-215 NHMe S-i-Pr H 4-Cl D-216 NHMe S-n-Bu H 4-Cl D-217 NHMe S-allyl H 4-Cl D-218 NHMe S-propargyl H 4-Cl D-219 NHMe SCH₂CF₃ H 4-Cl D-220 NHMe SCH₂CH₂F H 4-Cl D-221 NHEt SH H 4-F D-222 NHEt SMe H 4-Cl D-223 NHEt SEt H 4-Cl D-224 NHEt S-n-Pr H 4-Cl D-225 NHEt S-i-Pr H 4-Cl D-226 NHEt S-n-Bu H 4-Cl D-227 NHEt S-allyl H 4-Cl D-228 NHEt S-propargyl H 4-Cl D-229 NHEt SCH₂CF₃ H 4-Cl D-230 NHEt SCH₂CH₂F H 4-Cl D-231 NHPr SH H 4-Cl D-232 NHPr SMe H 4-Cl D-233 NHPr SEt H 4-Cl D-234 NHPr S-n-Pr H 4-Cl D-235 NHPr S-i-Pr H 4-Cl D-236 NHPr S-n-Bu H 4-Cl D-237 NHPr S-allyl H 4-Cl D-238 NHPr S-propargyl H 4-Cl D-239 NHPr SCH₂CF₃ H 4-Cl D-240 NHPr SCH₂CH₂F H 4-Cl D-241 NH-i-Pr SH H 4-Cl D-242 NH-i-Pr SMe H 4-Cl D-243 NH-i-Pr SEt H 4-Cl D-244 NH-i-Pr S-n-Pr H 4-Cl D-245 NH-i-Pr S-i-Pr H 4-Cl D-246 NH-i-Pr S-n-Bu H 4-Cl D-247 NH-i-Pr S-allyl H 4-Cl D-248 NH-i-Pr S-propargyl H 4-Cl D-249 NH-i-Pr SCH₂CF₃ H 4-Cl D-250 NH-i-Pr SCH₂CH₂F H 4-Cl D-251 NH-allyl SH H 4-Cl D-252 NH-allyl SMe H 4-Cl D-253 NH-allyl SEt H 4-Cl D-254 NH-allyl S-n-Pr H 4-Cl D-255 NH-allyl S-i-Pr H 4-Cl D-256 NH-allyl S-n-Bu H 4-Cl D-257 NH-allyl S-allyl H 4-Cl D-258 NH-allyl S-propargyl H 4-Cl D-259 NH-allyl SCH₂CF₃ H 4-Cl D-260 NH-allyl SCH₂CH₂F H 4-Cl D-261 NH-propargyl SH H 4-Cl D-262 NH-propargyl SMe H 4-Cl D-263 NH-propargyl SEt H 4-Cl D-264 NH-propargyl S-n-Pr H 4-Cl D-265 NH-propargyl S-i-Pr H 4-Cl D-266 NH-propargyl S-n-Bu H 4-Cl D-267 NH-propargyl S-allyl H 4-Cl D-268 NH-propargyl S-propargyl H 4-Cl D-269 NH-propargyl SCH₂CF₃ H 4-Cl D-270 NH-propargyl SCH₂CH₂F H 4-Cl D-271 NHCH₂CF₃ SH H 4-Cl D-272 NHCH₂CF₃ SMe H 4-Cl D-273 NHCH₂CF₃ SEt H 4-Cl D-274 NHCH₂CF₃ S-n-Pr H 4-Cl D-275 NHCH₂CF₃ S-i-Pr H 4-Cl D-276 NHCH₂CF₃ S-n-Bu H 4-Cl D-277 NHCH₂CF₃ S-allyl H 4-Cl D-278 NHCH₂CF₃ S-propargyl H 4-Cl D-279 NHCH₂CF₃ SCH₂CF₃ H 4-Cl D-280 NHCH₂CF₃ SCH₂CH₂F H 4-Cl D-281 NHCH₂CH₂F SH H 4-Cl D-282 NHCH₂CH₂F SMe H 4-Cl D-283 NHCH₂CH₂F SEt H 4-Cl D-284 NHCH₂CH₂F S-n-Pr H 4-Cl D-285 NHCH₂CH₂F S-i-Pr H 4-Cl D-286 NHCH₂CH₂F S-n-Bu H 4-Cl D-287 NHCH₂CH₂F S-allyl H 4-Cl D-288 NHCH₂CH₂F S-propargyl H 4-Cl D-289 NHCH₂CH₂F SCH₂CF₃ H 4-Cl D-290 NHCH₂CH₂F SCH₂CH₂F H 4-Cl D-291 NH-n-Bu SH H 4-Cl D-292 NH-n-Bu SMe H 4-Cl D-293 NH-n-Bu SEt H 4-Cl D-294 NH-n-Bu S-n-Pr H 4-Cl D-295 NH-n-Bu S-i-Pr H 4-Cl D-296 NH-n-Bu S-n-Bu H 4-Cl D-297 NH-n-Bu S-allyl H 4-Cl D-298 NH-n-Bu S-propargyl H 4-Cl D-299 NH-n-Bu SCH₂CF₃ H 4-Cl D-300 NH-n-Bu SCH₂CH₂F H 4-Cl

[0375] TABLE 10 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-301 NH₂ SH H 4-Me D-302 NH₂ SMe H 4-Me D-303 NH₂ SEt H 4-Me D-304 NH₂ S-n-Pr H 4-Me D-305 NH₂ S-i-Pr H 4-Me D-306 NH₂ S-n-Bu H 4-Me D-307 NH₂ S-allyl H 4-Me D-308 NH₂ S-propargyl H 4-Me D-309 NH₂ SCH₂CF₃ H 4-Me D-310 NH₂ SCH₂CH₂F H 4-Me D-311 NHMe SH H 4-Me D-312 NHMe SMe H 4-Me D-313 NHMe SEt H 4-Me D-314 NHMe S-n-Pr H 4-Me D-315 NHMe S-i-Pr H 4-Me D-316 NHMe S-n-Bu H 4-Me D-317 NHMe S-allyl H 4-Me D-318 NHMe S-propargyl H 4-Me D-319 NHMe SCH₂CF₃ H 4-Me D-320 NHMe SCH₂CH₂F H 4-Me D-321 NHEt SH H 4-Me D-322 NHEt SMe H 4-Me D-323 NHEt SEt H 4-Me D-324 NHEt S-n-Pr H 4-Me D-325 NHEt S-i-Pr H 4-Me D-326 NHEt S-n-Bu H 4-Me D-327 NHEt S-allyl H 4-Me D-328 NHEt S-propargyl H 4-Me D-329 NHEt SCH₂CF₃ H 4-Me D-330 NHEt SCH₂CH₂F H 4-Me D-331 NHPr SH H 4-Me D-332 NHPr SMe H 4-Me D-333 NHPr SEt H 4-Me D-334 NHPr S-n-Pr H 4-Me D-335 NHPr S-i-Pr H 4-Me D-336 NHPr S-n-Bu H 4-Me D-337 NHPr S-allyl H 4-Me D-338 NHPr S-propargyl H 4-Me D-339 NHPr SCH₂CF₃ H 4-Me D-340 NHPr SCH₂CH₂F H 4-Me D-341 NH-i-Pr SH H 4-Me D-342 NH-i-Pr SMe H 4-Me D-343 NH-i-Pr SEt H 4-Me D-344 NH-i-Pr S-n-Pr H 4-Me D-345 NH-i-Pr S-i-Pr H 4-Me D-346 NH-i-Pr S-n-Bu H 4-Me D-347 NH-i-Pr S-allyl H 4-Me D-348 NH-i-Pr S-propargyl H 4-Me D-349 NH-i-Pr SCH₂CF₃ H 4-Me D-350 NH-i-Pr SCH₂CH₂F H 4-Me D-351 NH-allyl SH H 4-Me D-352 NH-allyl SMe H 4-Me D-353 NH-allyl SEt H 4-Me D-354 NH-allyl S-n-Pr H 4-Me D-355 NH-allyl S-i-Pr H 4-Me D-356 NH-allyl S-n-Bu H 4-Me D-357 NH-allyl S-allyl H 4-Me D-358 NH-allyl S-propargyl H 4-Me D-359 NH-allyl SCH₂CF₃ H 4-Me D-360 NH-allyl SCH₂CH₂F H 4-Me D-361 NH-propargyl SH H 4-Me D-362 NH-propargyl SMe H 4-Me D-363 NH-propargyl SEt H 4-Me D-364 NH-propargyl S-n-Pr H 4-Me D-365 NH-propargyl S-i-Pr H 4-Me D-366 NH-propargyl S-n-Bu H 4-Me D-367 NH-propargyl S-allyl H 4-Me D-368 NH-propargyl S-propargyl H 4-Me D-369 NH-propargyl SCH₂CF₃ H 4-Me D-370 NH-propargyl SCH₂CH₂F H 4-Me D-371 NHCH₂CF₃ SH H 4-Me D-372 NHCH₂CF₃ SMe H 4-Me D-373 NHCH₂CF₃ SEt H 4-Me D-374 NHCH₂CF₃ S-n-Pr H 4-Me D-375 NHCH₂CF₃ S-i-Pr H 4-Me D-376 NHCH₂CF₃ S-n-Bu H 4-Me D-377 NHCH₂CF₃ S-allyl H 4-Me D-378 NHCH₂CF₃ S-propargyl H 4-Me D-379 NHCH₂CF₃ SCH₂CF₃ H 4-Me D-380 NHCH₂CF₃ SCH₂CH₂F H 4-Me D-381 NHCH₂CH₂F SH H 4-Me D-382 NHCH₂CH₂F SMe H 4-Me D-383 NHCH₂CH₂F SEt H 4-Me D-384 NHCH₂CH₂F S-n-Pr H 4-Me D-385 NHCH₂CH₂F S-i-Pr H 4-Me D-386 NHCH₂CH₂F S-n-Bu H 4-Me D-387 NHCH₂CH₂F S-allyl H 4-Me D-388 NHCH₂CH₂F S-propargyl H 4-Me D-389 NHCH₂CH₂F SCH₂CF₃ H 4-Me D-390 NHCH₂CH₂F SCH₂CH₂F H 4-Me D-391 NH-n-Bu SH H 4-Me D-392 NH-n-Bu SMe H 4-Me D-393 NH-n-Bu SEt H 4-Me D-394 NH-n-Bu S-n-Pr H 4-Me D-395 NH-n-Bu S-i-Pr H 4-Me D-396 NH-n-Bu S-n-Bu H 4-Me D-397 NH-n-Bu S-allyl H 4-Me D-398 NH-n-Bu S-propargyl H 4-Me D-399 NH-n-Bu SCH₂CF₃ H 4-Me D-400 NH-n-Bu SCH₂CH₂F H 4-Me

[0376] TABLE 11 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-401 NH₂ SH Me 2-NH₂ D-402 NH₂ SMe Me 2-NH₂ D-403 NH₂ SEt Me 2-NH₂ D-404 NH₂ S-n-Pr Me 2-NH₂ D-405 NH₂ S-i-Pr Me 2-NH₂ D-406 NH₂ S-n-Bu Me 2-NH₂ D-407 NH₂ S-allyl Me 2-NH₂ D-408 NH₂ S-propargyl Me 2-NH₂ D-409 NH₂ SCH₂CF₃ Me 2-NH₂ D-410 NH₂ SCH₂CH₂F Me 2-NH₂ D-411 NHMe SH Me 2-NH₂ D-412 NHMe SMe Me 2-NH₂ D-413 NHMe SEt Me 2-NH₂ D-414 NHMe S-n-Pr Me 2-NH₂ D-415 NHMe S-i-Pr Me 2-NH₂ D-416 NHMe S-n-Bu Me 2-NH₂ D-417 NHMe S-allyl Me 2-NH₂ D-418 NHMe S-propargyl Me 2-NH₂ D-419 NHMe SCH₂CF₃ Me 2-NH₂ D-420 NHMe SCH₂CH₂F Me 2-NH₂ D-421 NHEt SH Me 2-NH₂ D-422 NHEt SMe Me 2-NH₂ D-423 NHEt SEt Me 2-NH₂ D-424 NHEt S-n-Pr Me 2-NH₂ D-425 NHEt S-i-Pr Me 2-NH₂ D-426 NHEt S-n-Bu Me 2-NH₂ D-427 NHEt S-allyl Me 2-NH₂ D-428 NHEt S-propargyl Me 2-NH₂ D-429 NHEt SCH₂CF₃ Me 2-NH₂ D-430 NHEt SCH₂CH₂F Me 2-NH₂ D-431 NHPr SH Me 2-NH₂ D-432 NHPr SMe Me 2-NH₂ D-433 NHPr SEt Me 2-NH₂ D-434 NHPr S-n-Pr Me 2-NH₂ D-435 NHPr S-i-Pr Me 2-NH₂ D-436 NHPr S-n-Bu Me 2-NH₂ D-437 NHPr S-allyl Me 2-NH₂ D-438 NHPr S-propargyl Me 2-NH₂ D-439 NHPr SCH₂CF₃ Me 2-NH₂ D-440 NHPr SCH₂CH₂F Me 2-NH₂ D-441 NH-i-Pr SH Me 2-NH₂ D-442 NH-i-Pr SMe Me 2-NH₂ D-443 NH-i-Pr SEt Me 2-NH₂ D-444 NH-i-Pr S-n-Pr Me 2-NH₂ D-445 NH-i-Pr S-i-Pr Me 2-NH₂ D-446 NH-i-Pr S-n-Bu Me 2-NH₂ D-447 NH-i-Pr S-allyl Me 2-NH₂ D-448 NH-i-Pr S-propargyl Me 2-NH₂ D-449 NH-i-Pr SCH₂CF₃ Me 2-NH₂ D-450 NH-i-Pr SCH₂CH₂F Me 2-NH₂ D-451 NH-allyl SH Me 2-NH₂ D-452 NH-allyl SMe Me 2-NH₂ D-453 NH-allyl SEt Me 2-NH₂ D-454 NH-allyl S-n-Pr Me 2-NH₂ D-455 NH-allyl S-i-Pr Me 2-NH₂ D-456 NH-allyl S-n-Bu Me 2-NH₂ D-457 NH-allyl S-allyl Me 2-NH₂ D-458 NH-allyl S-propargyl Me 2-NH₂ D-459 NH-allyl SCH₂CF₃ Me 2-NH₂ D-460 NH-allyl SCH₂CH₂F Me 2-NH₂ D-461 NH-propargyl SH Me 2-NH₂ D-462 NH-propargyl SMe Me 2-NH₂ D-463 NH-propargyl SEt Me 2-NH₂ D-464 NH-propargyl S-n-Pr Me 2-NH₂ D-465 NH-propargyl S-i-Pr Me 2-NH₂ D-466 NH-propargyl S-n-Bu Me 2-NH₂ D-467 NH-propargyl S-allyl Me 2-NH₂ D-468 NH-propargyl S-propargyl Me 2-NH₂ D-469 NH-propargyl SCH₂CF₃ Me 2-NH₂ D-470 NH-propargyl SCH₂CH₂F Me 2-NH₂ D-471 NHCH₂CF₃ SH Me 2-NH₂ D-472 NHCH₂CF₃ SMe Me 2-NH₂ D-473 NHCH₂CF₃ SEt Me 2-NH₂ D-474 NHCH₂CF₃ S-n-Pr Me 2-NH₂ D-475 NHCH₂CF₃ S-i-Pr Me 2-NH₂ D-476 NHCH₂CF₃ S-n-Bu Me 2-NH₂ D-477 NHCH₂CF₃ S-allyl Me 2-NH₂ D-478 NHCH₂CF₃ S-propargyl Me 2-NH₂ D-479 NHCH₂CF₃ SCH₂CF₃ Me 2-NH₂ D-480 NHCH₂CF₃ SCH₂CH₂F Me 2-NH₂ D-481 NHCH₂CH₂F SH Me 2-NH₂ D-482 NHCH₂CH₂F SMe Me 2-NH₂ D-483 NHCH₂CH₂F SEt Me 2-NH₂ D-484 NHCH₂CH₂F S-n-Pr Me 2-NH₂ D-485 NHCH₂CH₂F S-i-Pr Me 2-NH₂ D-486 NHCH₂CH₂F S-n-Bu Me 2-NH₂ D-487 NHCH₂CH₂F S-allyl Me 2-NH₂ D-488 NHCH₂CH₂F S-propargyl Me 2-NH₂ D-489 NHCH₂CH₂F SCH₂CF₃ Me 2-NH₂ D-490 NHCH₂CH₂F SCH₂CH₂F Me 2-NH₂ D-491 NH-n-Bu SH Me 2-NH₂ D-492 NH-n-Bu SMe Me 2-NH₂ D-493 NH-n-Bu SEt Me 2-NH₂ D-494 NH-n-Bu S-n-Pr Me 2-NH₂ D-495 NH-n-Bu S-i-Pr Me 2-NH₂ D-496 NH-n-Bu S-n-Bu Me 2-NH₂ D-497 NH-n-Bu S-allyl Me 2-NH₂ D-498 NH-n-Bu S-propargyl Me 2-NH₂ D-499 NH-n-Bu SCH₂CF₃ Me 2-NH₂ D-500 NH-n-Bu SCH₂CH₂F Vie 2-NH₂

[0377] TABLE 12 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-501 NH₂ SH Et 4-NO₂ D-502 NH₂ SMe Et 4-NO₂ D-503 NH₂ SEt Et 4-NO₂ D-504 NH₂ S-n-Pr Et 4-NO₂ D-505 NH₂ S-i-Pr Et 4-NO₂ D-506 NH₂ S-n-Bu Et 4-NO₂ D-507 NH₂ S-allyl Et 4-NO₂ D-508 NH₂ S-propargyl Et 4-NO₂ D-509 NH₂ SCH₂CF₃ Et 4-NO₂ D-510 NH₂ SCH₂CH₂F Et 4-NO₂ D-511 NHMe SH Et 4-NO₂ D-512 NHMe SMe Et 4-NO₂ D-513 NHMe SEt Et 4-NO₂ D-514 NHMe S-n-Pr Et 4-NO₂ D-515 NHMe S-i-Pr Et 4-NO₂ D-516 NHMe S-n-Bu Et 4-NO₂ D-517 NHMe S-allyl Et 4-NO₂ D-518 NHMe S-propargyl Et 4-NO₂ D-519 NHMe SCH₂CF₃ Et 4-NO₂ D-520 NHMe SCH₂CH₂F Et 4-NO₂ D-521 NHEt SH Et 4-NO₂ D-522 NHEt SMe Et 4-NO₂ D-523 NHEt SEt Et 4-NO₂ D-524 NHEt S-n-Pr Et 4-NO₂ D-525 NHEt S-i-Pr Et 4-NO₂ D-526 NHEt S-n-Bu Et 4-NO₂ D-527 NHEt S-allyl Et 4-NO₂ D-528 NHEt S-propargyl Et 4-NO₂ D-529 NHEt SCH₂CF₃ Et 4-NO₂ D-530 NHEt SCH₂CH₂F Et 4-NO₂ D-531 NHPr SH Et 4-NO₂ D-532 NHPr SMe Et 4-NO₂ D-533 NHPr SEt Et 4-NO₂ D-534 NHPr S-n-Pr Et 4-NO₂ D-535 NHPr S-i-Pr Et 4-NO₂ D-536 NHPr S-n-Bu Et 4-NO₂ D-537 NHPr S-allyl Et 4-NO₂ D-538 NHPr S-propargyl Et 4-NO₂ D-539 NHPr SCH₂CF₃ Et 4-NO₂ D-540 NHPr SCH₂CH₂F Et 4-NO₂ D-541 NH-i-Pr SH Et 4-NO₂ D-542 NH-i-Pr SMe Et 4-NO₂ D-543 NH-i-Pr SEt Et 4-NO₂ D-544 NH-i-Pr S-n-Pr Et 4-NO₂ D-545 NH-i-Pr S-i-Pr Et 4-NO₂ D-546 NH-i-Pr S-n-Bu Et 4-NO₂ D-547 NH-i-Pr S-allyl Et 4-NO₂ D-548 NH-i-Pr S-propargyl Et 4-NO₂ D-549 NH-i-Pr SCH₂CF₃ Et 4-NO₂ D-550 NH-i-Pr SCH₂CH₂F Et 4-NO₂ D-551 NH-allyl SH Et 4-NO₂ D-552 NH-allyl SMe Et 4-NO₂ D-553 NH-allyl SEt Et 4-NO₂ D-554 NH-allyl S-n-Pr Et 4-NO₂ D-555 NH-allyl S-i-Pr Et 4-NO₂ D-556 NH-allyl S-n-Bu Et 4-NO₂ D-557 NH-allyl S-allyl Et 4-NO₂ D-558 NH-allyl S-propargyl Et 4-NO₂ D-559 NH-allyl SCH₂CF₃ Et 4-NO₂ D-560 NH-allyl SCH₂CH₂F Et 4-NO₂ D-561 NH-propargyl SH Et 4-NO₂ D-562 NH-propargyl SMe Et 4-NO₂ D-563 NH-propargyl SEt Et 4-NO₂ D-564 NH-propargyl S-n-Pr Et 4-NO₂ D-565 NH-propargyl S-i-Pr Et 4-NO₂ D-566 NH-propargyl S-n-Bu Et 4-NO₂ D-567 NH-propargyl S-allyl Et 4-NO₂ D-568 NH-propargyl S-propargyl Et 4-NO₂ D-569 NH-propargyl SCH₂CF₃ Et 4-NO₂ D-570 NH-propargyl SCH₂CH₂F Et 4-NO₂ D-571 NHCH₂CF₃ SH Et 4-NO₂ D-572 NHCH₂CF₃ SMe Et 4-NO₂ D-573 NHCH₂CF₃ SEt Et 4-NO₂ D-574 NHCH₂CF₃ S-n-Pr Et 4-NO₂ D-575 NHCH₂CF₃ S-i-Pr Et 4-NO₂ D-576 NHCH₂CF₃ S-n-Bu Et 4-NO₂ D-577 NHCH₂CF₃ S-allyl Et 4-NO₂ D-578 NHCH₂CF₃ S-propargyl Et 4-NO₂ D-579 NHCH₂CF₃ SCH₂CF₃ Et 4-NO₂ D-580 NHCH₂CF₃ SCH₂CH₂F Et 4-NO₂ D-581 NHCH₂CH₂F SH Et 4-NO₂ D-582 NHCH₂CH₂F SMe Et 4-NO₂ D-583 NHCH₂CH₂F SEt Et 4-NO₂ D-584 NHCH₂CH₂F S-n-Pr Et 4-NO₂ D-585 NHCH₂CH₂F S-i-Pr Et 4-NO₂ D-586 NHCH₂CH₂F S-n-Bu Et 4-NO₂ D-587 NHCH₂CH₂F S-allyl Et 4-NO₂ D-588 NHCH₂CH₂F S-propargyl Et 4-NO₂ D-589 NHCH₂CH₂F SCH₂CF₃ Et 4-NO₂ D-590 NHCH₂CH₂F SCH₂CH₂F Et 4-NO₂ D-591 NH-n-Bu SH Et 4-NO₂ D-592 NH-n-Bu SMe Et 4-NO₂ D-593 NH-n-Bu SEt Et 4-NO₂ D-594 NH-n-Bu S-n-Pr Et 4-NO₂ D-595 NH-n-Bu S-i-Pr Et 4-NO₂ D-596 NH-n-Bu S-n-Bu Et 4-NO₂ D-597 NH-n-Bu S-allyl Et 4-NO₂ D-598 NH-n-Bu S-propargyl Et 4-NO₂ D-599 NH-n-Bu SCH₂CF₃ Et 4-NO₂ D-600 NH-n-Bu SCH₂CH₂F Et 4-NO₂

[0378] TABLE 13 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-601 NH₂ SH Et 4-NH₂ D-602 NH₂ SMe Et 4-NH₂ D-603 NH₂ SEt Et 4-NH₂ D-604 NH₂ S-n-Pr Et 4-NH₂ D-605 NH₂ S-i-Pr Et 4-NH₂ D-606 NH₂ S-n-Bu Et 4-NH₂ D-607 NH₂ S-allyl Et 4-NH₂ D-608 NH₂ S-propargyl Et 4-NH₂ D-609 NH₂ SCH₂CF₃ Et 4-NH₂ D-610 NH₂ SCH₂CH₂F Et 4-NH₂ D-611 NHMe SH Et 4-NH₂ D-612 NHMe SMe Et 4-NH₂ D-613 NHMe SEt Et 4-NH₂ D-614 NHMe S-n-Pr Et 4-NH₂ D-615 NHMe S-i-Pr Et 4-NH₂ D-616 NHMe S-n-Bu Et 4-NH₂ D-617 NHMe S-allyl Et 4-NH₂ D-618 NHMe S-propargyl Et 4-NH₂ D-619 NHMe SCH₂CF₃ Et 4-NH₂ D-620 NHMe SCH₂CH₂F Et 4-NH₂ D-621 NHEt SH Et 4-NH₂ D-622 NHEt SMe Et 4-NH₂ D-623 NHEt SEt Et 4-NH₂ D-624 NHEt S-n-Pr Et 4-NH₂ D-625 NHEt S-i-Pr Et 4-NH₂ D-626 NHEt S-n-Bu Et 4-NH₂ D-627 NHEt S-allyl Et 4-NH₂ D-628 NHEt S-propargyl Et 4-NH₂ D-629 NHEt SCH₂CF₃ Et 4-NH₂ D-630 NHEt SCH₂CH₂F Et 4-NH₂ D-631 NHPr SH Et 4-NH₂ D-632 NHPr SMe Et 4-NH₂ D-633 NHPr SEt Et 4-NH₂ D-634 NHPr S-n-Pr Et 4-NH₂ D-635 NHPr S-i-Pr Et 4-NH₂ D-636 NHPr S-n-Bu Et 4-NH₂ D-637 NHPr S-allyl Et 4-NH₂ D-638 NHPr S-propargyl Et 4-NH₂ D-639 NHPr SCH₂CF₃ Et 4-NH₂ D-640 NHPr SCH₂CH₂F Et 4-NH₂ D-641 NH-i-Pr SH Et 4-NH₂ D-642 NH-i-Pr SMe Et 4-NH₂ D-643 NH-i-Pr SEt Et 4-NH₂ D-644 NH-i-Pr S-n-Pr Et 4-NH₂ D-645 NH-i-Pr S-i-Pr Et 4-NH₂ D-646 NH-i-Pr S-n-Bu Et 4-NH₂ D-647 NH-i-Pr S-allyl Et 4-NH₂ D-648 NH-i-Pr S-propargyl Et 4-NH₂ D-649 NH-i-Pr SCH₂CF₃ Et 4-NH₂ D-650 NH-i-Pr SCH₂CH₂F Et 4-NH₂ D-651 NH-allyl SH Et 4-NH₂ D-652 NH-allyl SMe Et 4-NH₂ D-653 NH-allyl SEt Et 4-NH₂ D-654 NH-allyl S-n-Pr Et 4-NH₂ D-655 NH-allyl S-i-Pr Et 4-NH₂ D-656 NH-allyl S-n-Bu Et 4-NH₂ D-657 NH-allyl S-allyl Et 4-NH₂ D-658 NH-allyl S-propargyl Et 4-NH₂ D-659 NH-allyl SCH₂CF₃ Et 4-NH₂ D-660 NH-allyl SCH₂CH₂F Et 4-NH₂ D-661 NH-propargyl SH Et 4-NH₂ D-662 NH-propargyl SMe Et 4-NH₂ D-663 NH-propargyl SEt Et 4-NH₂ D-664 NH-propargyl S-n-Pr Et 4-NH₂ D-665 NH-propargyl S-i-Pr Et 4-NH₂ D-666 NH-propargyl S-n-Bu Et 4-NH₂ D-667 NH-propargyl S-allyl Et 4-NH₂ D-668 NH-propargyl S-propargyl Et 4-NH₂ D-669 NH-propargyl SCH₂CF₃ Et 4-NH₂ D-670 NH-propargyl SCH₂CH₂F Et 4-NH₂ D-671 NHCH₂CF₃ SH Et 4-NH₂ D-672 NHCH₂CF₃ SMe Et 4-NH₂ D-673 NHCH₂CF₃ SEt Et 4-NH₂ D-674 NHCH₂CF₃ S-n-Pr Et 4-NH₂ D-675 NHCH₂CF₃ S-i-Pr Et 4-NH₂ D-676 NHCH₂CF₃ S-n-Bu Et 4-NH₂ D-677 NHCH₂CF₃ S-allyl Et 4-NH₂ D-678 NHCH₂CF₃ S-propargyl Et 4-NH₂ D-679 NHCH₂CF₃ SCH₂CF₃ Et 4-NH₂ D-680 NHCH₂CF₃ SCH₂CH₂F Et 4-NH₂ D-681 NHCH₂CH₂F SH Et 4-NH₂ D-682 NHCH₂CH₂F SMe Et 4-NH₂ D-683 NHCH₂CH₂F SEt Et 4-NH₂ D-684 NHCH₂CH₂F S-n-Pr Et 4-NH₂ D-685 NHCH₂CH₂F S-i-Pr Et 4-NH₂ D-686 NHCH₂CH₂F S-n-Bu Et 4-NH₂ D-687 NHCH₂CH₂F S-allyl Et 4-NH₂ D-688 NHCH₂CH₂F S-propargyl Et 4-NH₂ D-689 NHCH₂CH₂F SCH₂CF₃ Et 4-NH₂ D-690 NHCH₂CH₂F SCH₂CH₂F Et 4-NH₂ D-691 NH-n-Bu SH Et 4-NH₂ D-692 NH-n-Bu SMe Et 4-NH₂ D-693 NH-n-Bu SEt Et 4-NH₂ D-694 NH-n-Bu S-n-Pr Et 4-NH₂ D-695 NH-n-Bu S-i-Pr Et 4-NH₂ D-696 NH-n-Bu S-n-Bu Et 4-NH₂ D-697 NH-n-Bu S-allyl Et 4-NH₂ D-698 NH-n-Bu S-propargyl Et 4-NH₂ D-699 NH-n-Bu SCH₂CF₃ Et 4-NH₂ D-700 NH-n-Bu SCH₂CH₂F Et 4-NH₂

[0379] TABLE 14 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-701 NH₂ SH Me 4-NO₂ D-702 NH₂ SMe Me 4-OMe D-703 NH₂ SEt Me 4-NO₂ D-704 NH₂ S-n-Pr Me 4-NO₂ D-705 NH₂ S-i-Pr Me 4-NO₂ D-706 NH₂ S-n-Bu Me 4-NO₂ D-707 NH₂ S-allyl Me 4-NO₂ D-708 NH₂ S-propargyl Me 4-NO₂ D-709 NH₂ SCH₂CF₃ Me 4-NO₂ D-710 NH₂ SCH₂CH₂F Me 4-NO₂ D-711 NHMe SH Me 4-NO₂ D-712 NHMe SMe Me 4-OMe D-713 NHMe SEt Me 4-OMe D-714 NHMe S-n-Pr Me 4-OMe D-715 NHMe S-i-Pr Me 4-NO₂ D-716 NHMe S-n-Bu Me 4-NO₂ D-717 NHMe S-allyl Me 4-NO₂ D-718 NHMe S-propargyl Me 4-NO₂ D-719 NHMe SCH₂CF₃ Me 4-NO₂ D-720 NHMe SCH₂CH₂F Me 4-NO₂ D-721 NHEt SH Me 4-NO₂ D-722 NHEt SMe Me 4-OMe D-723 NHEt SEt Me 4-OMe D-724 NHEt S-n-Pr Me 4-OMe D-725 NHEt S-i-Pr Me 4-NO₂ D-726 NHEt S-n-Bu Me 4-NO₂ D-727 NHEt S-allyl Me 4-NO₂ D-728 NHEt S-propargyl Me 4-NO₂ D-729 NHEt SCH₂CF₃ Me 4-NO₂ D-730 NHEt SCH₂CH₂F Me 4-NO₂ D-731 NHPr SH Me 4-NO₂ D-732 NHPr SMe Me 4-OMe D-733 NHPr SEt Me 4-NO₂ D-734 NHPr S-n-Pr Me 4-NO₂ D-735 NHPr S-i-Pr Me 4-NO₂ D-736 NHPr S-n-Bu Me 4-NO₂ D-737 NHPr S-allyl Me 4-NO₂ D-738 NHPr S-propargyl Me 4-NO₂ D-739 NHPr SCH₂CF₃ Me 4-NO₂ D-740 NHPr SCH₂CH₂F Me 4-NO₂ D-741 NH-i-Pr SH Me 4-NO₂ D-742 NH-i-Pr SMe Me 4-NO₂ D-743 NH-i-Pr SEt Me 4-NO₂ D-744 NH-i-Pr S-n-Pr Me 4-NO₂ D-745 NH-i-Pr S-i-Pr Me 4-NO₂ D-746 NH-i-Pr S-n-Bu Me 4-NO₂ D-747 NH-i-Pr S-allyl Me 4-NO₂ D-748 NH-i-Pr S-propargyl Me 4-NO₂ D-749 NH-i-Pr SCH₂CF₃ Me 4-NO₂ D-750 NH-i-Pr SCH₂CH₂F Me 4-NO₂ D-751 NH-allyl SH Me 4-NO₂ D-752 NH-allyl SMe Me 4-NO₂ D-753 NH-allyl SEt Me 4-NO₂ D-754 NH-allyl S-n-Pr Me 4-NO₂ D-755 NH-allyl S-i-Pr Me 4-NO₂ D-756 NH-allyl S-n-Bu Me 4-NO₂ D-757 NH-allyl S-allyl Me 4-NO₂ D-758 NH-allyl S-propargyl Me 4-NO₂ D-759 NH-allyl SCH₂CF₃ Me 4-NO₂ D-760 NH-allyl SCH₂CH₂F Me 4-NO₂ D-761 NH-propargyl SH Me 4-NO₂ D-762 NH-propargyl SMe Me 4-NO₂ D-763 NH-propargyl SEt Me 4-NO₂ D-764 NH-propargyl S-n-Pr Me 4-NO₂ D-765 NH-propargyl S-i-Pr Me 4-NO₂ D-766 NH-propargyl S-n-Bu Me 4-NO₂ D-767 NH-propargyl S-allyl Me 4-NO₂ D-768 NH-propargyl S-propargyl Me 4-NO₂ D-769 NH-propargyl SCH₂CF₃ Me 4-NO₂ D-770 NH-propargyl SCH₂CH₂F Me 4-NO₂ D-771 NHCH₂CF₃ SH Me 4-NO₂ D-772 NHCH₂CF₃ SMe Me 4-OMe D-773 NHCH₂CF₃ SEt Me 4-NO₂ D-774 NHCH₂CF₃ S-n-Pr Me 4-NO₂ D-775 NHCH₂CF₃ S-i-Pr Me 4-NO₂ D-776 NHCH₂CF₃ S-n-Bu Me 4-NO₂ D-777 NHCH₂CF₃ S-allyl Me 4-NO₂ D-778 NHCH₂CF₃ S-propargyl Me 4-NO₂ D-779 NHCH₂CF₃ SCH₂CF₃ Me 4-NO₂ D-780 NHCH₂CF₃ SCH₂CH₂F Me 4-NO₂ D-781 NHCH₂CH₂F SH Me 4-NO₂ D-782 NHCH₂CH₂F SMe Me 4-NO₂ D-783 NHCH₂CH₂F SEt Me 4-NO₂ D-784 NHCH₂CH₂F S-n-Pr Me 4-NO₂ D-785 NHCH₂CH₂F S-i-Pr Me 4-NO₂ D-786 NHCH₂CH₂F S-n-Bu Me 4-NO₂ D-787 NHCH₂CH₂F S-allyl Me 4-NO₂ D-788 NHCH₂CH₂F S-propargyl Me 4-NO₂ D-789 NHCH₂CH₂F SCH₂CF₃ Me 4-NO₂ D-790 NHCH₂CH₂F SCH₂CH₂F Me 4-NO₃ D-791 NH-n-Bu SH Me 4-NO₂ D-792 NH-n-Bu SMe Me 4-NO₂ D-793 NH-n-Bu SEt Me 4-NO₂ D-794 NH-n-Bu S-n-Pr Me 4-NO₂ D-795 NH-n-Bu S-i-Pr Me 4-NO₂ D-796 NH-n-Bu S-n-Bu Me 4-NO₂ D-797 NH-n-Bu S-allyl Me 4-NO₂ D-798 NH-n-Bu S-propargyl Me 4-NO₂ D-799 NH-n-Bu SCH₂CF₃ Me 4-NO₂ D-800 NH-n-Bu SCH₂CH₂F Me 4-NO₂

[0380] TABLE 15 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-801 NH₂ SH Me 4-NH₂ D-802 NH₂ SMe Me 4-OMe D-803 NH₂ SEt Me 4-NH₂ D-804 NH₂ S-n-Pr Me 4-NH₂ D-805 NH₂ S-i-Pr Me 4-NH₂ D-806 NH₂ S-n-Bu Me 4-NH₂ D-807 NH₂ S-allyl Me 4-NH₂ D-808 NH₂ S-propargyl Me 4-NH₂ D-809 NH₂ SCH₂CF₃ Me 4-NH₂ D-810 NH₂ SCH₂CH₂F Me 4-NH₂ D-811 NHMe SH Me 4-NH₂ D-812 NHMe SMe Me 4-OMe D-813 NHMe SEt Me 4-OMe D-814 NHMe S-n-Pr Me 4-OMe D-815 NHMe S-i-Pr Me 4-NH₂ D-816 NHMe S-n-Bu Me 4-NH₂ D-817 NHMe S-allyl Me 4-NH₂ D-818 NHMe S-propargyl Me 4-NH₂ D-819 NHMe SCH₂CF₃ Me 4-NH₂ D-820 NHMe SCH₂CH₂F Me 4-NH₂ D-821 NHEt SH Me 4-NH₂ D-822 NHEt SMe Me 4-OMe D-823 NHEt SEt Me 4-OMe D-824 NHEt S-n-Pr Me 4-OMe D-825 NHEt S-i-Pr Me 4-NH₂ D-826 NHEt S-n-Bu Me 4-NH₂ D-827 NHEt S-allyl Me 4-NH₂ D-828 NHEt S-propargyl Me 4-NH₂ D-829 NHEt SCH₂CF₃ Me 4-NH₂ D-830 NHEt SCH₂CH₂F Me 4-NH₂ D-831 NHPr SH Me 4-NH₂ D-832 NHPr SMe Me 4-OMe D-833 NHPr SEt Me 4-NH₂ D-834 NHPr S-n-Pr Me 4-NH₂ D-835 NHPr S-i-Pr Me 4-NH₂ D-836 NHPr S-n-Bu Me 4-NH₂ D-837 NHPr S-allyl Me 4-NH₂ D-838 NHPr S-propargyl Me 4-NH₂ D-839 NHPr SCH₂CF₃ Me 4-NH₂ D-840 NHPr SCH₂CH₂F Me 4-NH₂ D-841 NH-i-Pr SH Me 4-NH₂ D-842 NH-i-Pr SMe Me 4-NH₂ D-843 NH-i-Pr SEt Me 4-NH₂ D-844 NH-i-Pr S-n-Pr Me 4-NH₂ D-845 NH-i-Pr S-i-Pr Me 4-NH₂ D-846 NH-i-Pr S-n-Bu Me 4-NH₂ D-847 NH-i-Pr S-allyl Me 4-NH₂ D-848 NH-i-Pr S-propargyl Me 4-NH₂ D-849 NH-i-Pr SCH₂CF₃ Me 4-NH₂ D-850 NH-i-Pr SCH₂CH₂F Me 4-NH₂ D-851 NH-allyl SH Me 4-NH₂ D-852 NH-allyl SMe Me 4-NH₂ D-853 NH-allyl SEt Me 4-NH₂ D-854 NH-allyl S-n-Pr Me 4-NH₂ D-855 NH-allyl S-i-Pr Me 4-NH₂ D-856 NH-allyl S-n-Bu Me 4-NH₂ D-857 NH-allyl S-allyl Me 4-NH₂ D-858 NH-allyl S-propargyl Me 4-NH₂ D-859 NH-allyl SCH₂CF₃ Me 4-NH₂ D-860 NH-allyl SCH₂CH₂F Me 4-NH₂ D-861 NH-propargyl SH Me 4-NH₂ D-862 NH-propargyl SMe Me 4-NHz D-863 NH-propargyl SEt Me 4-NH₂ D-864 NH-propargyl S-n-Pr Me 4-NH₂ D-865 NH-propargyl S-i-Pr Me 4-NH₂ D-866 NH-propargyl S-n-Bu Me 4-NH₂ D-867 NH-propargyl S-allyl Me 4-NH₂ D-868 NH-propargyl S-propargyl Me 4-NH₂ D-869 NH-propargyl SCH₂CF₃ Me 4-NH₂ D-870 NH-propargyl SCH₂CH₂F Me 4-NH₂ D-871 NHCH₂CF₃ SH Me 4-NH₂ D-872 NHCH₂CF₃ SMe Me 4-OMe D-873 NHCH₂CF₃ SEt Me 4-NH₂ D-874 NHCH₂CF₃ S-n-Pr Me 4-NH₂ D-875 NHCH₂CF₃ S-i-Pr Me 4-NH₂ D-876 NHCH₂CF₃ S-n-Bu Me 4-NH₂ D-877 NHCH₂CF₃ S-allyl Me 4-NH₂ D-878 NHCH₂CF₃ S-propargyl Me 4-NH₂ D-879 NHCH₂CF₃ SCH₂CF₃ Me 4-NH₂ D-880 NHCH₂CF₃ SCH₂CH₂F Me 4-NH₂ D-881 NHCH₂CH₂F SH Me 4-NH₂ D-882 NHCH₂CH₂F SMe Me 4-NH₂ D-883 NHCH₂CH₂F SEt Me 4-NH₂ D-884 NHCH₂CH₂F S-n-Pr Me 4-NH₂ D-885 NHCH₂CH₂F S-i-Pr Me 4-NH₂ D-886 NHCH₂CH₂F S-n-Bu Me 4-NH₂ D-887 NHCH₂CH₂F S-allyl Me 4-NH₂ D-888 NHCH₂CH₂F S-propargyl Me 4-NH₂ D-889 NHCH₂CH₂F SCH₂CF₃ Me 4-NH₂ D-890 NHCH₂CH₂F SCH₂CH₂F Me 4-NH₂ D-891 NH-n-Bu SH Me 4-NH₂ D-892 NH-n-Bu SMe Me 4-NH₂ D-893 NH-n-Bu SEt Me 4-NH₂ D-894 NH-n-Bu S-n-Pr Me 4-NH₂ D-895 NH-n-Bu S-i-Pr Me 4-NH₂ D-896 NH-n-Bu S-n-Bu Me 4-NH₂ D-897 NH-n-Bu S-allyl Me 4-NH₂ D-898 NH-n-Bu S-propargyl Me 4-NH₂ D-899 NH-n-Bu SCH₂CF₃ Me 4-NH₂ D-900 NH-n-Bu SCH₂CH₂F Me 4-NH₂

[0381] TABLE 16 Com- pound No. R₁₅ R¹⁶ R₁₇ R¹⁸ D-901 NH₂ OH H 4-NH₂ D-902 NH₂ OMe H 4-NH₂ D-903 NH₂ OEt H 4-NH₂ D-904 NH₂ O-n-Pr H 4-NH₂ D-905 NH₂ O-i-Pr H 4-NH₂ D-906 NH₂ O-n-Bu H 4-NH₂ D-907 NH₂ O-allyl H 4-NH₂ D-908 NH₂ O-propargyl H 4-NH₂ D-909 NH₂ OCH₂CF₃ H 4-NH₂ D-910 NH₂ OCH₂CH₂F H 4-NH₂ D-911 NHMe OH H 4-NH₂ D-912 NHMe OMe H 4-NH₂ D-913 NHMe OEt H 4-NH₂ D-914 NHMe O-n-Pr H 4-NH₂ D-915 NHMe O-i-Pr H 4-NH₂ D-916 NHMe O-n-Bu H 4-NH₂ D-917 NHMe O-allyl H 4-NH₂ D-918 NHMe O-propargyl H 4-NH₂ D-919 NHMe OCH₂CF₃ H 4-NH₂ D-920 NHMe OCH₂CH₂F H 4-NH₂ D-921 NHEt OH H 4-NH₂ D-922 NHEt OMe H 4-NH₂ D-923 NHEt OEt H 4-NH₂ D-924 NHEt O-n-Pr H 4-NH₂ D-925 NHEt O-i-Pr H 4-NH₂ D-926 NHEt O-n-Bu H 4-NH₂ D-927 NHEt O-allyl H 4-NH₂ D-928 NHEt O-propargyl H 4-NH₂ D-929 NHEt OCH₂CF₃ H 4-NH₂ D-930 NHEt OCH₂CH₂F H 4-NH₂ D-931 NHPr OH H 4-NH₂ D-932 NHPr OMe H 4-NH₂ D-933 NHPr OEt H 4-NH₂ D-934 NHPr O-n-Pr H 4-NH₂ D-935 NHPr O-i-Pr H 4-NH₂ D-936 NHPr O-n-Bu H 4-NH₂ D-937 NHPr O-allyl H 4-NH₂ D-938 NHPr O-propargyl H 4-NH₂ D-939 NHPr OCH₂CF₃ H 4-NH₂ D-940 NHPr OCH₂CH₂F H 4-NH₂ D-941 NH-i-Pr OH H 4-NH₂ D-942 NH-i-Pr OMe H 4-NH₂ D-943 NH-i-Pr OEt H 4-NH₂ D-944 NH-i-Pr O-n-Pr H 4-NH₂ D-945 NH-i-Pr O-i-Pr H 4-NH₂ D-946 NH-i-Pr O-n-Bu H 4-NH₂ D-947 NH-i-Pr O-allyl H 4-NH₂ D-948 NH-i-Pr O-propargyl H 4-NH₂ D-949 NH-i-Pr OCH₂CF₃ H 4-NH₂ D-950 NH-i-Pr OCH₂CH₂F H 4-NH₂ D-951 NH-allyl OH H 4-NH₂ D-952 NH-allyl OMe H 4-NH₂ D-953 NH-allyl OEt H 4-NH₂ D-954 NH-allyl O-n-Pr H 4-NH₂ D-955 NH-allyl O-i-Pr H 4-NH₂ D-956 NH-allyl O-n-Bu H 4-NH₂ D-957 NH-allyl O-allyl H 4-NH₂ D-958 NH-allyl O-propargyl H 4-NH₂ D-959 NH-allyl OCH₂CF₃ H 4-NH₂ D-960 NH-allyl OCH₂CH₂F H 4-NH₂ D-961 NH-propargyl OH H 4-NH₂ D-962 NH-propargyl OMe H 4-NH₂ D-963 NH-propargyl OEt H 4-NH₂ D-964 NH-propargyl O-n-Pr H 4-NH₂ D-965 NH-propargyl O-i-Pr H 4-NH₂ D-966 NH-propargyl O-n-Bu H 4-NH₂ D-967 NH-propargyl O-allyl H 4-NH₂ D-968 NH-propargyl O-propargyl H 4-NH₂ D-969 NH-propargyl OCH₂CF₃ H 4-NH₂ D-970 NH-propargyl OCH₂CH₂F H 4-NH₂ D-971 NHCH₂CF₃ OH H 4-NH₂ D-972 NHCH₂CF₃ OMe H 4-NH₂ D-973 NHCH₂CF₃ OEt H 4-NH₂ D-974 NHCH₂CF₃ O-n-Pr H 4-NH₂ D-975 NHCH₂CF₃ O-i-Pr H 4-NH₂ D-976 NHCH₂CF₃ O-n-Bu H 4-NH₂ D-977 NHCH₂CF₃ O-allyl H 4-NH₂ D-978 NHCH₂CF₃ O-propargyl H 4-NH₂ D-979 NHCH₂CF₃ OCH₂CF₃ H 4-NH₂ D-980 NHCH₂CF₃ OCH₂CH₂F H 4-NH₂ D-981 NHCH₂CH₂F OH H 4-NH₂ D-982 NHCH₂CH₂F OMe H 4-NH₂ D-983 NHCH₂CH₂F OEt H 4-NH₂ D-984 NHCH₂CH₂F O-n-Pr H 4-NH₂ D-985 NHCH₂CH₂F O-i-Pr H 4-NH₂ D-986 NHCH₂CH₂F O-n-Bu H 4-NH₂ D-987 NHCH₂CH₂F O-allyl H 4-NH₂ D-988 NHCH₂CH₂F O-propargyl H 4-NH₂ D-989 NHCH₂CH₂F OCH₂CF₃ H 4-NH₂ D-990 NHCH₂CH₂F OCH₂CH₂F H 4-NH₂ D-991 NH-n-Bu OH H 4-NH₂ D-992 NH-n-Bu OMe H 4-NH₂ D-993 NH-n-Bu OEt H 4-NH₂ D-994 NH-n-Bu O-n-Pr H 4-NH₂ D-995 NH-n-Bu O-i-Pr H 4-NH₂ D-996 NH-n-Bu O-n-Bu H 4-NH₂ D-997 NH-n-Bu O-allyl H 4-NH₂ D-998 NH-n-Bu O-propargyl H 4-NH₂ D-999 NH-n-Bu OCH₂CF₃ H 4-NH₂ D-1000 NH-n-Bu OCH₂CH₂F H 4-NH₂

[0382] TABLE 17 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-1001 NH₂ OH H 4-NO₂ D-1002 NH₂ OMe H 4-NO₂ D-1003 NH₂ OEt H 4-NO₂ D-1004 NH₂ O-n-Pr H 4-NO₂ D-1005 NH₂ O-i-Pr H 4-NO₂ D-1006 NH₂ O-n-Bu H 4-NO₂ D-1007 NH₂ O-allyl H 4-NO₂ D-1008 NH₂ O-propargyl H 4-NO₂ D-1009 NH₂ OCH₂CF₃ H 4-NO₂ D-1010 NH₂ OCH₂CH₂F H 4-NO₂ D-1011 NHMe OH H 4-NO₂ D-1012 NHMe OMe H 4-NO₂ D-1013 NHMe OEt H 4-NO₂ D-1014 NHMe O-n-Pr H 4-NO₂ D-1015 NHMe O-i-Pr H 4-NO₂ D-1016 NHMe O-n-Bu H 4-NO₂ D-1017 NHMe O-allyl H 4-NO₂ D-1018 NHMe O-propargyl H 4-NO₂ D-1019 NHMe OCH₂CF₃ H 4-NO₂ D-1020 NHMe OCH₂CH₂F H 4-NO₂ D-1021 NHEt OH H 4-NO₂ D-1022 NHEt OMe H 4-NO₂ D-1023 NHEt OEt H 4-NO₂ D-1024 NHEt O-n-Pr H 4-NO₂ D-1025 NHEt O-i-Pr H 4-NO₂ D-1026 NHEt O-n-Bu H 4-NO₂ D-1027 NHEt O-allyl H 4-NO₂ D-1028 NHEt O-propargyl H 4-NO₂ D-1029 NHEt OCH₂CF₃ H 4-NO₂ D-1030 NHEt OCH₂CH₂F H 4-NO₂ D-1031 NHPr OH H 4-NO₂ D-1032 NHPr OMe H 4-NO₂ D-1033 NHPr OEt H 4-NO₂ D-1034 NHPr O-n-Pr H 4-NO₂ D-1035 NHPr O-i-Pr H 4-NO₂ D-1036 NHPr O-n-Bu H 4-NO₂ D-1037 NHPr O-allyl H 4-NO₂ D-1038 NHPr O-propargyl H 4-NO₂ D-1039 NHPr OCH₂CF₃ H 4-NO₂ D-1040 NHPr OCH₂CH₂F H 4-NO₂ D-1041 NH-i-Pr OH H 4-NO₂ D-1042 NH-i-Pr OMe H 4-NO₂ D-1043 NH-i-Pr OEt H 4-NO₂ D-1044 NH-i-Pr O-n-Pr H 4-NO₂ D-1045 NH-i-Pr O-i-Pr H 4-NO₂ D-1046 NH-i-Pr O-n-Bu H 4-NO₂ D-1047 NH-i-Pr O-allyl H 4-NO₂ D-1048 NH-i-Pr O-propargyl H 4-NO₂ D-1049 NH-i-Pr OCH₂CF₃ H 4-NO₂ D-1050 NH-i-Pr OCH₂CH₂F H 4-NO₂ D-1051 NH-allyl OH H 4-NO₂ D-1052 NH-allyl OMe H 4-NO₂ D-1053 NH-allyl OEt H 4-NO₂ D-1054 NH-allyl O-n-Pr H 4-NO₂ D-1055 NH-allyl O-i-Pr H 4-NO₂ D-1056 NH-allyl O-n-Bu H 4-NO₂ D-1057 NH-allyl O-allyl H 4-NO₂ D-1058 NH-allyl O-propargyl H 4-NO₂ D-1059 NH-allyl OCH₂CF₃ H 4-NO₂ D-1060 NH-allyl OCH₂CH₂F H 4-NO₂ D-1061 NH-propargyl OH H 4-NO₂ D-1062 NH-propargyl OMe H 4-NO₂ D-1063 NH-propargyl OEt H 4-NO₂ D-1064 NH-propargyl O-n-Pr H 4-NO₂ D-1065 NH-propargyl O-i-Pr H 4-NO₂ D-1066 NH-propargyl O-n-Bu H 4-NO₂ D-1067 NH-propargyl O-allyl H 4-NO₂ D-1068 NH-propargyl O-propargyl H 4-NO₂ D-1069 NH-propargyl OCH₂CF₃ H 4-NO₂ D-1070 NH-propargyl OCH₂CH₂F H 4-NO₂ D-1071 NHCH₂CF₃ OH H 4-NO₂ D-1072 NHCH₂CF₃ OMe H 4-NO₂ D-1073 NHCH₂CF₃ OEt H 4-NO₂ D-1074 NHCH₂CF₃ O-n-Pr H 4-NO₂ D-1075 NHCH₂CF₃ O-i-Pr H 4-NO₂ D-1076 NHCH₂CF₃ O-n-Bu H 4-NO₂ D-1077 NHCH₂CF₃ O-allyl H 4-NO₂ D-1078 NHCH₂CF₃ O-propargyl H 4-NO₂ D-1079 NHCH₂CF₃ OCH₂CF₃ H 4-NO₂ D-1080 NHCH₂CF₃ OCH₂CH₂F H 4-NO₂ D-1081 NHCH₂CH₂F OH H 4-NO₂ D-1082 NHCH₂CH₂F OMe H 4-NO₂ D-1083 NHCH₂CH₂F OEt H 4-NO₂ D-1084 NHCH₂CH₂F O-n-Pr H 4-NO₂ D-1085 NHCH₂CH₂F O-i-Pr H 4-NO₂ D-1086 NHCH₂CH₂F O-n-Bu H 4-NO₂ D-1087 NHCH₂CH₂F O-allyl H 4-NO₂ D-1088 NHCH₂CH₂F O-propargyl H 4-NO₂ D-1089 NHCH₂CH₂F OCH₂CF₃ H 4-NO₂ D-1090 NHCH₂CH₂F OCH₂CH₂F H 4-NO₂ D-1091 NH-n-Bu OH H 4-NO₂ D-1092 NH-n-Bu OMe H 4-NO₂ D-1093 NH-n-Bu OEt H 4-NO₂ D-1094 NH-n-Bu O-n-Pr H 4-NO₂ D-1095 NH-n-Bu O-i-Pr H 4-NO₂ D-1096 NH-n-Bu O-n-Bu H 4-NO₂ D-1097 NH-n-Bu O-allyl H 4-NO₂ D-1098 NH-n-Bu O-propargyl H 4-NO₂ D-1099 NH-n-Bu OCH₂CF₃ H 4-NO₂ D-1100 NH-n-Bu OCH₂CH₂F H 4-NO₂

[0383] TABLE 18 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-1101 NH₂ OH Me 4-NH₂ D-1102 NH₂ OMe Me 4-NH₂ D-1103 NH₂ OEt Me 4-NH₂ D-1104 NH₂ O-n-Pr Me 4-NH₂ D-1105 NH₂ O-i-Pr Me 4-NH₂ D-1106 NH₂ O-n-Bu Me 4-NH₂ D-1107 NH₂ O-allyl Me 4-NH₂ D-1108 NH₂ O-propargyl Me 4-NH₂ D-1109 NH₂ OCH₂CF₃ Me 4-NH₂ D-1110 NH₂ OCH₂CH₂F Me 4-NH₂ D-1111 NHMe OH Me 4-NH₂ D-1112 NHMe OMe Me 4-NH₂ D-1113 NHMe OEt Me 4-NH₂ D-1114 NHMe O-n-Pr Me 4-NH₂ D-1115 NHMe O-i-Pr Me 4-NH₂ D-1116 NHMe O-n-Bu Me 4-NH₂ D-1117 NHMe O-allyl Me 4-NH₂ D-1118 NHMe O-propargyl Me 4-NH₂ D-1119 NHMe OCH₂CF₃ Me 4-NH₂ D-1120 NHMe OCH₂CH₂F Me 4-NH₂ D-1121 NHEt OH Me 2-NH₂ D-1122 NHEt OMe Me 4-NH₂ D-1123 NHEt OEt Me 4-NH₂ D-1124 NHEt O-n-Pr Me 4-NH₂ D-1125 NHEt O-i-Pr Me 4-NH₂ D-1126 NHEt O-n-Bu Me 4-NH₂ D-1127 NHEt O-allyl Me 4-NH₂ D-1128 NHEt O-propargyl Me 4-NH₂ D-1129 NHEt OCH₂CF₃ Me 4-NH₂ D-1130 NHEt OCH₂CH₂F Me 4-NH₂ D-1131 NHPr OH Me 4-NH₂ D-1132 NHPr OMe Me 4-NH₂ D-1133 NHPr OEt Me 4-NH₂ D-1134 NHPr O-n-Pr Me 4-NH₂ D-1135 NHPr O-i-Pr Me 4-NH₂ D-1136 NHPr O-n-Bu Me 4-NH₂ D-1137 NHPr O-allyl Me 4-NH₂ D-1138 NHPr O-propargyl Me 4-NH₂ D-1139 NHPr OCH₂CF₃ Me 4-NH₂ D-1140 NHPr OCH₂CH₂F Me 4-NH₂ D-1141 NH-i-Pr OH Me 4-NH₂ D-1142 NH-i-Pr OMe Me 4-NH₂ D-1143 NH-i-Pr OEt Me 4-NH₂ D-1144 NH-i-Pr O-n-Pr Me 4-NH₂ D-1145 NH-i-Pr O-i-Pr Me 4-NH₂ D-1146 NH-i-Pr O-n-Bu Me 4-NH₂ D-1147 NH-i-Pr O-allyl Me 4-NH₂ D-1148 NH-i-Pr O-propargyl Me 4-NH₂ D-1149 NH-i-Pr OCH₂CF₃ Me 4-NH₂ D-1150 NH-i-Pr OCH₂CH₂F Me 4-NH₂ D-1151 NH-allyl OH Me 4-NH₂ D-1152 NH-allyl OMe Me 4-NH₂ D-1153 NH-allyl OEt Me 4-NH₂ D-1154 NH-allyl O-n-Pr Me 4-NH₂ D-1155 NH-allyl O-i-Pr Me 4-NH₂ D-1156 NH-allyl O-n-Bu Me 4-NH₂ D-1157 NH-allyl O-allyl Me 4-NH₂ D-1158 NH-allyl O-propargyl Me 4-NH₂ D-1159 NH-allyl OCH₂CF₃ Me 4-NH₂ D-1160 NH-allyl OCH₂CH₂F Me 4-NH₂ D-1161 NH-propargyl OH Me 4-NH₂ D-1162 NH-propargyl OMe Me 4-NH₂ D-1163 NH-propargyl OEt Me 4-NH₂ D-1164 NH-propargyl O-n-Pr Me 4-NH₂ D-1165 NH-propargyl O-i-Pr Me 4-NH₂ D-1166 NH-propargyl O-n-Bu Me 4-NH₂ D-1167 NH-propargyl O-allyl Me 4-NH₂ D-1168 NH-propargyl O-propargyl Me 4-NH₂ D-1169 NH-propargyl OCH₂CF₃ Me 4-NH₂ D-1170 NH-propargyl OCH₂CH₂F Me 4-NH₂ D-1171 NHCH₂CF₃ OH Me 4-NH₂ D-1172 NHCH₂CF₃ OMe Me 4-NH₂ D-1173 NHCH₂CF₃ OEt Me 4-NH₂ D-1174 NHCH₂CF₃ O-n-Pr Me 4-NH₂ D-1175 NHCH₂CF₃ O-i-Pr Me 4-NH₂ D-1176 NHCH₂CF₃ O-n-Bu Me 4-NH₂ D-1177 NHCH₂CF₃ O-allyl Me 4-NH₂ D-1178 NHCH₂CF₃ O-propargyl Me 4-NH₂ D-1179 NHCH₂CF₃ OCH₂CF₃ Me 4-NH₂ D-1180 NHCH₂CF₃ OCH₂CH₂F Me 4-NH₂ D-1181 NHCH₂CH₂F OH Me 4-NH₂ D-1182 NHCH₂CH₂F OMe Me 4-NH₂ D-1183 NHCH₂CH₂F OEt Me 4-NH₂ D-1184 NHCH₂CH₂F O-n-Pr Me 4-NH₂ D-1185 NHCH₂CH₂F O-i-Pr Me 4-NH₂ D-1186 NHCH₂CH₂F O-n-Bu Me 4-NH₂ D-1187 NHCH₂CH₂F O-allyl Me 4-NH₂ D-1188 NHCH₂CH₂F O-propargyl Me 4-NH₂ D-1189 NHCH₂CH₂F OCH₂CF₃ Me 4-NH₂ D-1190 NHCH₂CH₂F OCH₂CH₂F Me 4-NH₂ D-1191 NH-n-Bu OH Me 4-NH₂ D-1192 NH-n-Bu OMe Me 4-NH₂ D-1193 NH-n-Bu OEt Me 4-NH₂ D-1194 NH-n-Bu O-n-Pr Me 4-NH₂ D-1195 NH-n-Bu O-i-Pr Me 4-NH₂ D-1196 NH-n-Bu O-n-Bu Me 4-NH₂ D-1197 NH-n-Bu O-allyl Me 4-NH₂ D-1198 NH-n-Bu O-propargyl Me 4-NH₂ D-1199 NH-n-Bu OCH₂CF₃ Me 4-NH₂ D-1200 NH-n-Bu OCH₂CH₂F Me 4-NH₂

[0384] TABLE 19 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-1201 NH₂ OH Me 4-NO₂ D-1202 NH₂ OMe Me 4-NO₂ D-1203 NH₂ OEt Me 4-NO₂ D-1204 NH₂ O-n-Pr Me 4-NO₂ D-1205 NH₂ O-i-Pr Me 4-NO₂ D-1206 NH₂ O-n-Bu Me 4-NO₂ D-1207 NH₂ O-allyl Me 4-NO₂ D-1208 NH₂ O-propargyl Me 4-NO₂ D-1209 NH₂ OCH₂CF₃ Me 4-NO₂ D-1210 NH₂ OCH₂CH₂F Me 4-NO₂ D-1211 NHMe OH Me 4-NO₂ D-1212 NHMe OMe Me 4-OMe D-1213 NHMe OEt Me 4-Cl D-1214 NHMe O-n-Pr Me 4-NO₂ D-1215 NHMe O-i-Pr Me 4-OMe D-1216 NHMe O-n-Bu Me 4-NO₂ D-1217 NHMe O-allyl Me 4-NO₂ D-1218 NHMe O-propargyl Me 4-NO₂ D-1219 NHMe OCH₂CF₃ Me 4-NO₂ D-1220 NHMe OCH₂CH₂F Me 4-NO₂ D-1221 NHEt OH Me 4-Me D-1222 NHEt OMe Me 4-OMe D-1223 NHEt OEt Me 4-OMe D-1224 NHEt O-n-Pr Me 4-NO₂ D-1225 NHEt O-i-Pr Me 4-OMe D-1226 NHEt O-n-Bu Me 4-NO₂ D-1227 NHEt O-allyl Me 4-NO₂ D-1228 NHEt O-propargyl Me 4-NO₂ D-1229 NHEt OCH₂CF₃ Me 4-NO₂ D-1230 NHEt OCH₂CH₂F Me 4-NO₂ D-1231 NHPr OH Me 4-OMe D-1232 NHPr OMe Me 4-NO₂ D-1233 NHPr OEt Me 4-NO₂ D-1234 NHPr O-n-Pr Me 4-NO₂ D-1235 NHPr O-i-Pr Me 4-NO₂ D-1236 NHPr O-n-Bu Me 4-NO₂ D-1237 NHPr O-allyl Me 4-NO₂ D-1238 NHPr O-propargyl Me 4-NO₂ D-1239 NHPr OCH₂CF₃ Me 4-NO₂ D-1240 NHPr OCH₂CH₂F Me 4-NO₂ D-1241 NH-i-Pr OH Me 4-NO₂ D-1242 NH-i-Pr OMe Me 4-NO₂ D-1243 NH-i-Pr OEt Me 4-NO₂ D-1244 NH-i-Pr O-n-Pr Me 4-NO₂ D-1245 NH-i-Pr O-i-Pr Me 4-NO₂ D-1246 NH-i-Pr O-n-Bu Me 4-NO₂ D-1247 NH-i-Pr O-allyl Me 4-NO₂ D-1248 NH-i-Pr O-propargyl Me 4-NO₂ D-1249 NH-i-Pr OCH₂CF₃ Me 4-NO₂ D-1250 NH-i-Pr OCH₂CH₂F Me 4-NO₂ D-1251 NH-allyl OH Me 4-NO₂ D-1252 NH-allyl OMe Me 4-NO₂ D-1253 NH-allyl OEt Me 4-NO₂ D-1254 NH-allyl O-n-Pr Me 4-NO₂ D-1255 NH-allyl O-i-Pr Me 4-NO₂ D-1256 NH-allyl O-n-Bu Me 4-NO₂ D-1257 NH-allyl O-allyl Me 4-NO₂ D-1258 NH-allyl O-propargyl Me 4-NO₂ D-1259 NH-allyl OCH₂CF₃ Me 4-NO₂ D-1260 NH-allyl OCH₂CH₂F Me 4-NO₂ D-1261 NH-propargyl OH Me 4-NO₂ D-1262 NH-propargyl OMe Me 4-NO₂ D-1263 NH-propargyl OEt Me 4-NO₂ D-1264 NH-propargyl O-n-Pr Me 4-NO₂ D-1265 NH-propargyl O-i-Pr Me 4-NO₂ D-1266 NH-propargyl O-n-Bu Me 4-NO₂ D-1267 NH-propargyl O-allyl Me 4-NO₂ D-1268 NH-propargyl O-propargyl Me 4-NO₂ D-1269 NH-propargyl OCH₂CF₃ Me 4-NO₂ D-1270 NH-propargyl OCH₂CH₂F Me 4-NO₂ D-1271 NHCH₂CF₃ OH Me 4-NH₂ D-1272 NHCH₂CF₃ OMe Me 4-NO₂ D-1273 NHCH₂CF₃ OEt Me 4-NO₂ D-1274 NHCH₂CF₃ O-n-Pr Me 4-NO₂ D-1275 NHCH₂CF₃ O-i-Pr Me 4-NO₂ D-1276 NHCH₂CF₃ O-n-Bu Me 4-NO₂ D-1277 NHCH₂CF₃ O-allyl Me 4-NO₂ D-1278 NHCH₂CF₃ O-propargyl Me 4-NO₂ D-1279 NHCH₂CF₃ OCH₂CF₃ Me 4-NO₂ D-1280 NHCH₂CF₃ OCH₂CH₂F Me 4-NO₂ D-1281 NHCH₂CH₂F OH Me 4-NO₂ D-1282 NHCH₂CH₂F OMe Me 4-NO₂ D-1283 NHCH₂CH₂F OEt Me 4-NO₂ D-1284 NHCH2CH₂F O-n-Pr Me 4-NO₂ D-1285 NHCH₂CH₂F O-i-Pr Me 4-NO₂ D-1286 NHCH₂CH₂F O-n-Bu Me 4-NO₂ D-1287 NHCH₂CH₂F O-allyl Me 4-NO₂ D-1288 NHCH₂CH₂F O-propargyl Me 4-NO₂ D-1289 NHCH₂CH₂F OCH₂CF₃ Me 4-NO₂ D-1290 NHCH₂CH₂F OCH₂CH₂F Me 4-NO₂ D-1291 NH-n-Bu OH Me 4-NO₂ D-1292 NH-n-Bu OMe Me 4-NO₂ D-1293 NH-n-Bu OEt Me 4-NO₂ D-1294 NH-n-Bu O-n-Pr Me 4-NO₂ D-1295 NH-n-Bu O-i-Pr Me 4-NO₂ D-1296 NH-n-Bu O-n-Bu Me 4-NO₂ D-1297 NH-n-Bu O-allyl Me 4-NO₂ D-1298 NH-n-Bu O-propargyl Me 4-NO₂ D-1299 NH-n-Bu OCH₂CF₃ Me 4-NO₂ D-1300 NH-n-Bu OCH₂CH₂F Me 4-NO₂

[0385] TABLE 20 Comp- ound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-1301 NH₂ NHOH Me 4-NH₂ D-1302 NH₂ NHOMe Me 4-NH₂ D-1303 NH₂ NHOEt Me 4-NH₂ D-1304 NH₂ NHNHz Me 4-NH₂ D-1305 NH₂ NHNMe₂ Me 4-NH₂ D-1306 NH₂ NHNHMe Me 4-NH₂ D-1307 NH₂ NHNHEt Me 4-NH₂ D-1308 NH₂ NMeNH₂ Me 4-NH₂ D-1309 NH₂ NHCN Me 4-NH₂ D-1310 NH₂ NHN0₂ Me 4-NH₂ D-1311 NHMe NHOH Me 4-NH₂ D-1312 NHMe NHOMe Me 4-NH₂ D-1313 NHMe NHOEt Me 4-NH₂ D-1314 NHMe NHNH₂ Me 4-NH₂ D-1315 NHMe NHNMe₂ Me 4-NH₂ D-1316 NHMe NHNHMe Me 4-NH₂ D-1317 NHMe NHNHEt Me 4-NH₂ D-1318 NHMe NMeNH₂ Me 4-NH₂ D-1319 NHMe NHCN Me 4-NH₂ D-1320 NHMe NHNO₂ Me 4-NH₂ D-1321 NHEt NHOH Me 4-NH₂ D-1322 NHEt NHOMe Me 4-NH₂ D-1323 NHEt NHOEt Me 4-NH₂ D-1324 NHEt NHNH₂ Me 4-NH₂ D-1325 NHEt NHNMe₂ Me 4-NH₂ D-1326 NHEt NHNHMe Me 4-NH₂ D-1327 NHEt NHNHEt Me 4-NH₂ D-1328 NHEt NMeNH₂ Me 4-NH₂ D-1329 NHEt NHCN Me 4-NH₂ D-1330 NHEt NHNO₂ Me 4-NH₂ D-1331 NH-i-Pr NHOH Me 4-NH₂ D-1332 NH-i-Pr NHOMe Me 4-NH₂ D-1333 NH-i-Pr NHOEt Me 4-NH₂ D-1334 NH-i-Pr NHNH₂ Me 4-NH₂ D-1335 NH-i-Pr NHNMe₂ Me 4-NH₂ D-1336 NH-i-Pr NHNHMe Me 4-NH₂ D-1337 NH-i-Pr NHNHEt Me 4-NH₂ D-1338 NH-i-Pr NMeNH₂ Me 4-NH₂ D-1339 NH-i-Pr NHCN Me 4-NH₂ D-1340 NH-i-Pr NHNO₂ Me 4-NH₂ D-1341 NH-allyl NHOH Me 4-NH₂ D-1342 NH-allyl NHOMe Me 4-NH₂ D-1343 NH-allyl NHOEt Me 4-NH₂ D-1344 NH-allyl NHNH₂ Me 4-NH₂ D-1345 NH-allyl NHNMe₂ Me 4-NH₂ D-1346 NH-allyl NHNHMe Me 4-NH₂ D-1347 NH-allyl NHNHEt Me 4-NH₂ D-1348 NH-allyl NMeNH₂ Me 4-NH₂ D-1349 NH-allyl NHCN Me 4-NH₂ D-1350 NH-allyl NHNO₂ Me 4-NH₂ D-1351 NH-propargyl NHOH Me 4-NH₂ D-1352 NH-propargyl NHOMe Me 4-NH₂ D-1353 NH-propargyl NHOEt Me 4-NH₂ D-1354 NH-propargyl NHNH₂ Me 4-NH₂ D-1355 NH-propargyl NHNMe₂ Me 4-NH₂ D-1356 NH-propargyl NHNHMe Me 4-NH₂ D-1357 NH-propargyl NHNHEt Me 4-NH₂ D-1358 NH-propargyl NMeNH₂ Me 4-NH₂ D-1359 NH-propargyl NHCN Me 4-NH₂ D-1360 NH-propargyl NHNO₂ Me 4-NH₂ D-1361 NHCH₂CH₂F NHOH Me 4-NH₂ D-1362 NHCH₂CH₂F NHOMe Me 4-NH₂ D-1363 NHCH₂CH₂F NHOEt Me 4-NH₂ D-1364 NHCH₂CH₂F NHNH₂ Me 4-NH₂ D-1365 NHCH₂CH₂F NHNMe₂ Me 4-NH₂ D-1366 NHCH₂CH₂F NHNHMe Me 4-NH₂ D-1367 NHCH₂CH₂F NHNHEt Me 4-NH₂ D-1368 NHCH₂CH₂F NMeNH₂ Me 4-NH₂ D-1369 NHCH₂CH₂F NHCN Me 4-NH₂ D-1370 NHCH₂CH₂F NHNO₂ Me 4-NH₂ D-1371 NHCH₂CF₃ NHOH Me 4-NH₂ D-1372 NHCH₂CF₃ NHOMe Me 4-NH₂ D-1373 NHCH₂CF₃ NHOEt Me 4-NH₂ D-1374 NHCH₂CF₃ NHNH₂ Me 4-NH₂ D-1375 NHCH₂CF₃ NHNMe₂ Me 4-NH₂ D-1376 NHCH₂CF₃ NHNHMe Me 4-NH₂ D-1377 NHCH₂CF₃ NHNHEt Me 4-NH₂ D-1378 NHCH₂CF₃ NMeNH₂ Me 4-NH₂ D-1379 NHCH₂CF₃ NHCN Me 4-NH₂ D-1380 NHCH₂CF₃ NHNO₂ Me 4-NH₂ D-1381 SMe NHOH Me 4-NH₂ D-1382 SMe NHOMe Me 4-NH₂ D-1383 SMe NHOEt Me 4-NH₂ D-1384 SMe NHNH₂ Me 4-NH₂ D-1385 SMe NHNMe₂ Me 4-NH₂ D-1386 SMe NHNHMe Me 4-NH₂ D-1387 SMe NHNHEt Me 4-NH₂ D-1388 SMe NMeNH₂ Me 4-NH₂ D-1389 SMe NHCN Me 4-NH₂ D-1390 SMe NHNO₂ Me 4-NH₂ D-1391 SEt NHOH Me 4-NH₂ D-1392 SEt NHOMe Me 4-NH₂ D-1393 SEt NHOEt Me 4-NH₂ D-1394 SEt NHNH₂ Me 4-NH₂ D-1395 SEt NHNMe₂ Me 4-NH₂ D-1396 SEt NHNHMe Me 4-NH₂ D-1397 SEt NHNHEt Me 4-NH₂ D-1398 SEt NMeNH₂ Me 4-NH₂ D-1399 SEt NHCN Me 4-NH₂ D-1400 SEt NHNO₂ Me 4-NH₂

[0386] TABLE 21 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-1401 NH₂ NHOH Me 4-NO₂ D-1402 NH₂ NHOMe Me 4-NO₂ D-1403 NH₂ NHOEt Me 4-NO₂ D-1404 NH₂ NHNH₂ Me 4-NO₂ D-1405 NH₂ NHNMe₂ Me 4-NO₂ D-1406 NH₂ NHNHMe Me 4-NO₂ D-1407 NH₂ NHNHEt Me 4-NO₂ D-1408 NH₂ NMeNH₂ Me 4-NO₂ D-1409 NH₂ NHCN Me 4-NO₂ D-1410 NH₂ NHNO₂ Me 4-NO₂ D-1411 NHMe NHOH Me 4-NO₂ D-1412 NHMe NHOMe Me 4-Cl D-1413 NHMe NHOEt Me 4-NO₂ D-1414 NHMe NHNH₂ Me 4-NO₂ D-1415 NHMe NHNMe₂ Me 4-NO₂ D-1416 NHMe NHNHMe Me 4-NO₂ D-1417 NHMe NHNHEt Me 4-NO₂ D-1418 NHMe NMeNH₂ Me 4-NO₂ D-1419 NHMe NHCN Me 4-NO₂ D-1420 NHMe NHNO₂ Me 4-NO₂ D-1421 NHEt NHOH Me 4-NO₂ D-1422 NHEt NHOMe Me 4-NO₂ D-1423 NHEt NHOEt Me 4-NO₂ D-1424 NHEt NHNH₂ Me 4-NO₂ D-1425 NHEt NHNMe₂ Me 4-NO₂ D-1426 NHEt NHNHMe Me 4-NO₂ D-1427 NHEt NHNHEt Me 4-NO₂ D-1428 NHEt NMeNH₂ Me 4-NO₂ D-1429 NHEt NHCN Me 4-NO₂ D-1430 NHEt NHNO₂ Me 4-NO₂ D-1431 NH-i-Pr NHOH Me 4-NO₂ D-1432 NH-i-Pr NHOMe Me 4-NO₂ D-1433 NH-i-Pr NHOEt Me 4-NO₂ D-1434 NH-i-Pr NHNH₂ Me 4-NO₂ D-1435 NH-i-Pr NHNMe₂ Me 4-NO₂ D-1436 NH-i-Pr NHNHMe Me 4-NO₂ D-1437 NH-i-Pr NHNHEt Me 4-NO₂ D-1438 NH-i-Pr NMeNH₂ Me 4-NO₂ D-1439 NH-i-Pr NHCN Me 4-NO₂ D-1440 NH-i-Pr NHNO₂ Me 4-NO₂ D-1441 NH-allyl NHOH Me 4-NO₂ D-1442 NH-allyl NHOMe Me 4-NO₂ D-1443 NH-allyl NHOEt Me 4-NO₂ D-1444 NH-allyl NHNH₂ Me 4-NO₂ D-1445 NH-allyl NHNMe₂ Me 4-NO₂ D-1446 NH-allyl NHNHMe Me 4-NO₂ D-1447 NH-allyl NHNHEt Me 4-NO₂ D-1448 NH-allyl NMeNH₂ Me 4-NO₂ D-1449 NH-allyl NHCN Me 4-NO₂ D-1450 NH-allyl NHNO₂ Me 4-NO₂ D-1451 NH-propargyl NHOH Me 4-NO₂ D-1452 NH-propargyl NHOMe Me 4-NO₂ D-1453 NH-propargyl NHOEt Me 4-NO₂ D-1454 NH-propargyl NHNH₂ Me 4-NO₂ D-1455 NH-propargyl NHNMe₂ Me 4-NO₂ D-1456 NH-propargyl NHNHMe Me 4-NO₂ D-1457 NH-propargyl NHNHEt Me 4-NO₂ D-1458 NH-propargyl NMeNH₂ Me 4-NO₂ D-1459 NH-propargyl NHCN Me 4-NO₂ D-1460 NH-propargyl NHNO₂ Me 4-NO₂ D-1461 NHCH₂CH₂F NHOH Me 4-NO₂ D-1462 NHCH₂CH₂F NHOMe Me 4-NO₂ D-1463 NHCH₂CH₂F NHOEt Me 4-NO₂ D-1464 NHCH₂CH₂F NHNH₂ Me 4-NO₂ D-1465 NHCH₂CH₂F NHNMe₂ Me 4-NO₂ D-1466 NHCH₂CH₂F NHNHMe Me 4-NO₂ D-1467 NHCH₂CH₂F NHNHEt Me 4-NO₂ D-1468 NHCH₂CH₂F NMeNH₂ Me 4-NO₂ D-1469 NHCH₂CH₂F NHCN Me 4-NO₂ D-1470 NHCH₂CH₂F NHNO₂ Me 4-NO₂ D-1471 NHCH₂CF₃ NHOH Me 4-NO₂ D-1472 NHCH₂CF₃ NHOMe Me 4-NO₂ D-1473 NHCH₂CF₃ NHOEt Me 4-NO₂ D-1474 NHCH₂CF₃ NHNH₂ Me 4-NO₂ D-1475 NHCH₂CF₃ NHNMe₂ Me 4-NO₂ D-1476 NHCH₂CF₃ NHNHMe Me 4-NO₂ D-1477 NHCH₂CF₃ NHNHEt Me 4-NO₂ D-1478 NHCH₂CF₃ NMeNH₂ Me 4-NO₂ D-1479 NHCH₂CF₃ NHCN Me 4-NO₂ D-1480 NHCH₂CF₃ NHNO₂ Me 4-NO₂ D-1481 SMe NHOH Me 4-NO₂ D-1482 SMe NHOMe Me 4-NO₂ D-1483 SMe NHOEt Me 4-NO₂ D-1484 SMe NHNH₂ Me 4-NO₂ D-1485 SMe NHNMe₂ Me 4-NO₂ D-1486 SMe NHNHMe Me 4-NO₂ D-1487 SMe NHNHEt Me 4-NO₂ D-1488 SMe NMeNH₂ Me 4-NO₂ D-1489 SMe NHCN Me 4-NO₂ D-1490 SMe NHNO₂ Me 4-NO₂ D-1491 SEt NHOH Me 4-NO₂ D-1492 SEt NHOMe Me 4-NO₂ D-1493 SEt NHOEt Me 4-NO₂ D-1494 SEt NHNH₂ Me 4-NO₂ D-1495 SEt NHNMe₂ Me 4-NO₂ D-1496 SEt NHNHMe Me 4-NO₂ D-1497 SEt NHNHEt Me 4-NO₂ D-1498 SEt NMeNH₂ Me 4-NO₂ D-1499 SEt NHCN Me 4-NO₂ D-1500 SEt NHNO₂ Me 4-NO₂

[0387] TABLE 22 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-1501 NH₂ NHOH H 4-NH₂ D-1502 NH₂ NHOMe H 4-NH₂ D-1503 NH₂ NHOEt H 4-NH₂ D-1504 NH₂ NHNH₂ H 4-NH₂ D-1505 NH₂ NHNMe₂ H 4-NH₂ D-1506 NH₂ NHNHMe H 4-NH₂ D-1507 NH₂ NHNHEt H 4-NH₂ D-1508 NH₂ NMeNH₂ H 4-NH₂ D-1509 NH₂ NHCN H 4-NH₂ D-1510 NH₂ NHNO₂ H 4-NH₂ D-1511 NHMe NHOH H 4-NH₂ D-1512 NHMe NHOMe H 4-NH₂ D-1513 NHMe NHOEt H 4-NH₂ D-1514 NHMe NHNH₂ H 4-NH₂ D-1515 NHMe NHNMe₂ H 4-NH₂ D-1516 NHMe NHNHMe H 4-NH₂ D-1517 NHMe NHNHEt H 4-NH₂ D-1518 NHMe NMeNH₂ H 4-NH₂ D-1519 NHMe NHCN H 4-NH₂ D-1520 NHMe NHNO₂ H 4-NH₂ D-1521 NHEt NHOH H 4-NH₂ D-1522 NHEt NHOMe H 4-NH₂ D-1523 NHEt NHOEt H 4-NH₂ D-1524 NHEt NHNH₂ H 4-NH₂ D-1525 NHEt NHNMe₂ H 4-NH₂ D-1526 NHEt NHNHMe H 4-NH₂ D-1527 NHEt NHNHEt H 4-NH₂ D-1528 NHEt NMeNH₂ H 4-NH₂ D-1529 NHEt NHCN H 4-NH₂ D-1530 NHEt NHNO₂ H 4-NH₂ D-1531 NH-i-Pr NHOH H 4-NH₂ D-1532 NH-i-Pr NHOMe H 4-NH₂ D-1533 NH-i-Pr NHOEt H 4-NH₂ D-1534 NH-i-Pr NHNH₂ H 4-NH₂ D-1535 NH-i-Pr NHNMe₂ H 4-NH₂ D-1536 NH-i-Pr NHNHMe H 4-NH₂ D-1537 NH-i-Pr NHNHEt H 4-NH₂ D-1538 NH-i-Pr NMeNH₂ H 4-NH₂ D-1539 NH-i-Pr NHCN H 4-NH₂ D-1540 NH-i-Pr NHNO₂ H 4-NH₂ D-1541 NH-allyl NHOH H 4-NH₂ D-1542 NH-allyl NHOMe H 4-NH₂ D-1543 NH-allyl NHOEt H 4-NH₂ D-1544 NH-allyl NHNH₂ H 4-NH₂ D-1545 NH-allyl NHNMe₂ H 4-NH₂ D-1546 NH-allyl NHNHMe H 4-NH₂ D-1547 NH-allyl NHNHEt H 4-NH₂ D-1548 NH-allyl NMeNH₂ H 4-NH₂ D-1549 NH-allyl NHCN H 4-NH₂ D-1550 NH-allyl NHNO₂ H 4-NH₂ D-1551 NH-propargyl NHOH H 4-NH₂ D-1552 NH-propargyl NHOMe H 4-NH₂ D-1553 NH-propargyl NHOEt H 4-NH₂ D-1554 NH-propargyl NHNH₂ H 4-NH₂ D-1555 NH-propargyl NHNMe₂ H 4-NH₂ D-1556 NH-propargyl NHNHMe H 4-NH₂ D-1557 NH-propargyl NHNHEt H 4-NH₂ D-1558 NH-propargyl NMeNH₂ H 4-NH₂ D-1559 NH-propargyl NHCN H 4-NH₂ D-1560 NH-propargyl NHNO₂ H 4-NH₂ D-1561 NHCH₂CH₂F NHOH H 4-NH₂ D-1562 NHCH₂CH₂F NHOMe H 4-NH₂ D-1563 NHCH₂CH₂F NHOEt H 4-NH₂ D-1564 NHCH₂CH₂F NHNH₂ H 4-NH₂ D-1565 NHCH₂CH₂F NHNMe₂ H 4-NH₂ D-1566 NHCH₂CH₂F NHNHMe H 4-NH₂ D-1567 NHCH₂CH₂F NHNHEt H 4-NH₂ D-1568 NHCH₂CH₂F NMeNH₂ H 4-NH₂ D-1569 NHCH₂CH₂F NHCN H 4-NH₂ D-1570 NHCH₂CH₂F NHNO₂ H 4-NH₂ D-1571 NHCH₂CF₃ NHOH H 4-NH₂ D-1572 NHCH₂CF₃ NHOMe H 4-NH₂ D-1573 NHCH₂CF₃ NHOEt H 4-NH₂ D-1574 NHCH₂CF₃ NHNH₂ H 4-NH₂ D-1575 NHCH₂CF₃ NHNMe₂ H 4-NH₂ D-1576 NHCH₂CF₃ NHNHMe H 4-NH₂ D-1577 NHCH₂CF₃ NHNHEt H 4-NH₂ D-1578 NHCH₂CF₃ NMeNH₂ H 4-NH₂ D-1579 NHCH₂CF₃ NHCN H 4-NH₂ D-1580 NHCH₂CF₃ NHNO₂ H 4-NH₂ D-1581 SMe NHOH H 4-NH₂ D-1582 SMe NHOMe H 4-NH₂ D-1583 SMe NHOEt H 4-NH₂ D-1584 SMe NHNH₂ H 4-NH₂ D-1585 SMe NHNMe₂ H 4-NH₂ D-1586 SMe NHNHMe H 4-NH₂ D-1587 SMe NHNHEt H 4-NH₂ D-1588 SMe NMeNH₂ H 4-NH₂ D-1589 SMe NHCN H 4-NH₂ D-1590 SMe NHNO₂ H 4-NH₂ D-1591 SEt NHOH H 4-NH₂ D-1592 SEt NHOMe H 4-NH₂ D-1593 SEt NHOEt H 4-NH₂ D-1594 SEt NHNH₂ H 4-NH₂ D-1595 SEt NHNMe₂ H 4-NH₂ D-1596 SEt NHNHMe H 4-NH₂ D-1597 SEt NHNHEt H 4-NH₂ D-1598 SEt NMeNH₂ H 4-NH₂ D-1599 SEt NHCN H 4-NH₂ D-1600 SEt NHNO₂ H 4-NH₂

[0388] TABLE 23 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ D-1601 NH₂ NHOH H 4-NO₂ D-1602 NH₂ NHOMe H 4-NO₂ D-1603 NH₂ NHOEt H 4-NO₂ D-1604 NH₂ NHNH₂ H 4-NO₂ D-1605 NH₂ NHNMe₂ H 4-NO₂ D-1606 NH₂ NHNHMe H 4-NO₂ D-1607 NH₂ NHNHEt H 4-NO₂ D-1608 NH₂ NMeNH₂ H 4-NO₂ D-1609 NH₂ NHCN H 4-NO₂ D-1610 NH₂ NHNO₂ H 4-NO₂ D-1611 NHMe NHOH H 4-NO₂ D-1612 NHMe NHOMe H 4-Cl D-1613 NHMe NHOEt H 4-NO₂ D-1614 NHMe NHNH₂ H 4-NO₂ D-1615 NHMe NHNMe₂ H 4-NO₂ D-1616 NHMe NHNHMe H 4-NO₂ D-1617 NHMe NHNHEt H 4-NO₂ D-1618 NHMe NMeNH₂ H 4-NO₂ D-1619 NHMe NHCN H 4-NO₂ D-1620 NHMe NHNO₂ H 4-NO₂ D-1621 NHEt NHOH H 4-NO₂ D-1622 NHEt NHOMe H 4-NO₂ D-1623 NHEt NHOEt H 4-NO₂ D-1624 NHEt NHNH₂ H 4-NO₂ D-1625 NHEt NHNMe₂ H 4-NO₂ D-1626 NHEt NHNHMe H 4-NO₂ D-1627 NHEt NHNHEt H 4-NO₂ D-1628 NHEt NMeNH₂ H 4-NO₂ D-1629 NHEt NHCN H 4-NO₂ D-1630 NHEt NHNO₂ H 4-NO₂ D-1631 NH-i-Pr NHOH H 4-NO₂ D-1632 NH-i-Pr NHOMe H 4-NO₂ D-1633 NH-i-Pr NHOEt H 4-NO₂ D-1634 NH-i-Pr NHNH₂ H 4-NO₂ D-1635 NH-i-Pr NHNMe₂ H 4-NO₂ D-1636 NH-i-Pr NHNHMe H 4-NO₂ D-1637 NH-i-Pr NHNHEt H 4-NO₂ D-1638 NH-i-Pr NMeNH₂ H 4-NO₂ D-1639 NH-i-Pr NHCN H 4-NO₂ D-1640 NH-i-Pr NHNO₂ H 4-NO₂ D-1641 NH-allyl NHOH H 4-NO₂ D-1642 NH-allyl NHOMe H 4-NO₂ D-1643 NH-allyl NHOEt H 4-NO₂ D-1644 NH-allyl NHNH₂ H 4-NO₂ D-1645 NH-allyl NHNMe₂ H 4-NO₂ D-1646 NH-allyl NHNHMe H 4-NO₂ D-1647 NH-allyl NHNHEt H 4-NO₂ D-1648 NH-allyl NMeNH₂ H 4-NO₂ D-1649 NH-allyl NHCN H 4-NO₂ D-1650 NH-allyl NHNO₂ H 4-NO₂ D-1651 NH-propargyl NHOH H 4-NO₂ D-1652 NH-propargyl NHOMe H 4-NO₂ D-1653 NH-propargyl NHOEt H 4-NO₂ D-1654 NH-propargyl NHNH₂ H 4-NO₂ D-1655 NH-propargyl NHNMe₂ H 4-NO₂ D-1656 NH-propargyl NHNHMe H 4-NO₂ D-1657 NH-propargyl NHNHEt H 4-NO₂ D-1658 NH-propargyl NMeNH₂ H 4-NO₂ D-1659 NH-propargyl NHCN H 4-NO₂ D-1660 NH-propargyl NHNO₂ H 4-NO₂ D-1661 NHCH₂CH₂F NHOH H 4-NO₂ D-1662 NHCH₂CH₂F NHOMe H 4-NO₂ D-1663 NHCH₂CH₂F NHOEt H 4-NO₂ D-1664 NHCH₂CH₂F NHNH₂ H 4-NO₂ D-1665 NHCH₂CH₂F NHNMe₂ H 4-NO₂ D-1666 NHCH₂CH₂F NHNHMe H 4-NO₂ D-1667 NHCH₂CH₂F NHNHEt H 4-NO₂ D-1668 NHCH₂CH₂F NMeNH₂ H 4-NO₂ D-1669 NHCH₂CH₂F NHCN H 4-NO₂ D-1670 NHCH₂CH₂F NHNO₂ H 4-NO₂ D-1671 NHCH₂CF₃ NHOH H 4-NO₂ D-1672 NHCH₂CF₃ NHOMe H 4-NO₂ D-1673 NHCH₂CF₃ NHOEt H 4-NO₂ D-1674 NHCH₂CF₃ NHNH₂ H 4-NO₂ D-1675 NHCH₂CF₃ NHNMe₂ H 4-NO₂ D-1676 NHCH₂CF₃ NHNHMe H 4-NO₂ D-1677 NHCH₂CF₃ NHNHEt H 4-NO₂ D-1678 NHCH₂CF₃ NMeNH₂ H 4-NO₂ D-1679 NHCH₂CF₃ NHCN H 4-NO₂ D-1680 NHCH₂CF₃ NHNO₂ H 4-NO₂ D-1681 SMe NHOH H 4-NO₂ D-1682 SMe NHOMe H 4-NO₂ D-1683 SMe NHOEt H 4-NO₂ D-1684 SMe NHNH₂ H 4-NO₂ D-1685 SMe NHNMe₂ H 4-NO₂ D-1686 SMe NHNHMe H 4-NO₂ D-1687 SMe NHNHEt H 4-NO₂ D-1688 SMe NMeNH₂ H 4-NO₂ D-1689 SMe NHCN H 4-NO₂ D-1690 SMe NHNO₂ H 4-NO₂ D-1691 SEt NHOH H 4-NO₂ D-1692 SEt NHOMe H 4-NO₂ D-1693 SEt NHOEt H 4-NO₂ D-1694 SEt NHNH₂ H 4-NO₂ D-1695 SEt NHNMe₂ H 4-NO₂ D-1696 SEt NHNHMe H 4-NO₂ D-1697 SEt NHNHEt H 4-NO₂ D-1698 SEt NMeNH₂ H 4-NO₂ D-1699 SEt NHCN H 4-NO₂ D-1700 SEt NHNO₂ H 4-NO₂

[0389] TABLE 24 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ E-1 —S(CH₂)₃NH— H 4-NO₂ E-2 —S(CH₂)₃NH— H 4-NH₂ E-3 —S(CH₂)₃NH— H 4-Cl E-4 —S(CH₂)₃NH— H 4-OMe E-5 —S(CH₂)₃NH— H 4-Me E-6 —S(CH₂)₃NH— Me 2-NH₂ E-7 —S(CH₂)₃NH— Me 4-NH₂ E-8 —S(CH₂)₃NH— Me 4-Cl E-9 —S(CH₂)₃NH— Me 4-OMe E-10 —S(CH₂)₃NH— Me 4-Me E-11 —S(CH₂)₃NH— Et 4-NO₂ E-12 —S(CH₂)₃NH— Et 4-NH₂ E-13 —S(CH₂)₃NH— Et 4-Cl E-14 —S(CH₂)₃NH— Et 4-OMe E-15 —S(CH₂)₃NH— Et 4-Me E-16 —S(CH₂)₂NH— H 4-NO₂ E-17 —S(CH₂)₂NH— H 4-NH₂ E-18 —S(CH₂)₂NH— H 4-Cl E-19 —S(CH₂)₂NH— H 4-OMe E-20 —S(CH₂)₂NH— H 4-Me E-21 —S(CH₂)₂NH— Me 2-NH₂ E-22 —S(CH₂)₂NH— Me 4-NH₂ E-23 —S(CH₂)₂NH— Me 4-Cl E-24 —S(CH₂)₂NH— Me 4-OMe E-25 —S(CH₂)₂NH— Me 4-Me E-26 —S(CH₂)₂NH— Et 4-NO₂ E-27 —S(CH₂)₂NH— Et 4-NH₂ E-28 —S(CH₂)₂NH— Et 4-Cl E-29 —S(CH₂)₂NH— Et 4-OMe E-30 —S(CH₂)₂NH— Et 4-Me E-31 —O(CH₂)₃NH— H 4-NO₂ E-32 —O(CH₂)₃NH— H 4-NH₂ E-33 —O(CH₂)₃NH— H 4-Cl E-34 —O(CH₂)₃NH— H 4-OMe E-35 —O(CH₂)₃NH— H 4-Me E-36 —O(CH₂)₃NH— Me 4-NO₂ E-37 —O(CH₂)₃NH— Me 4-NH₂ E-38 —O(CH₂)₃NH— Me 4-Cl E-39 —O(CH₂)₃NH— Me 4-OMe E-40 —O(CH₂)₃NH— Me 4-Me E-41 —O(CH₂)₃NH— Et 4-NO₂ E-42 —O(CH₂)₃NH— Et 4-NH₂ E-43 —O(CH₂)₃NH— Et 4-Cl E-44 —O(CH₂)₃NH— Et 4-OMe E-45 —O(CH₂)₃NH— Et 4-Me E-46 —O(CH₂)₂NH— H 4-NO₂ E-47 —O(CH₂)₂NH— H 4-NH₂ E-48 —O(CH₂)₂NH— H 4-Cl E-49 —O(CH₂)₂NH— H 4-OMe E-50 —O(CH₂)₂NH— H 4-Me E-51 —O(CH₂)₂NH— Me 4-NO₂ E-52 —O(CH₂)₂NH— Me 4-NH₂ E-53 —O(CH₂)₂NH— Me 4-Cl E-54 —O(CH₂)₂NH— Me 4-OMe E-55 —O(CH₂)₂NH— Me 4-Me E-56 —O(CH₂)₂NH— Et 4-NO₂ E-57 —O(CH₂)₂NH— Et 4-NH₂ E-58 —O(CH₂)₂NH— Et 4-Cl E-59 —O(CH₂)₂NH— Et 4-OMe E-60 —O(CH₂)₂NH— Et 4-Me

[0390] Compounds F-1 to F-800 shown in Tablse 25 to Table 32 are able to synthesize in a manner similar to those described in Example 22 or Example 23.

[0391] Table 25 to Table 32

TABLE 25 Comp- ound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ F-1 NH₂ SH H 4-NH₂ F-2 NH₂ SMe H 4-NH₂ F-3 NH₂ SEt H 4-NH₂ F-4 NH₂ S-n-Pr H 4-NH₂ F-5 NH₂ S-i-Pr H 4-NH₂ F-6 NH₂ S-n-Bu H 4-NH₂ F-7 NH₂ S-allyl H 4-NH₂ F-8 NH₂ S-propargyl H 4-NH₂ F-9 NH₂ SCH₂CF₃ H 4-NH₂ F-10 NH₂ SCH₂CH₂F H 4-NH₂ F-11 NHMe SH H 4-NH₂ F-12 NHMe SMe H 4-NH₂ F-13 NHMe SEt H 4-NH₂ F-14 NHMe S-n-Pr H 4-NH₂ F-15 NHMe S-i-Pr H 4-NH₂ F-16 NHMe S-n-Bu H 4-NH₂ F-17 NHMe S-allyl H 4-NH₂ F-18 NHMe S-propargyl H 4-NH₂ F-19 NHMe SCH₂CF₃ H 4-NH₂ F-20 NHMe SCH₂CH₂F H 4-NH₂ F-21 NHEt SH H 4-NH₂ F-22 NHEt SMe H 4-NH₂ F-23 NHEt SEt H 4-NH₂ F-24 NHEt S-n-Pr H 4-NH₂ F-25 NHEt S-i-Pr H 4-NH₂ F-26 NHEt S-n-Bu H 4-NH₂ F-27 NHEt S-allyl H 4-NH₂ F-28 NHEt S-propargyl H 4-NH₂ F-29 NHEt SCH₂CF₃ H 4-NH₂ F-30 NHEt SCH₂CH₂F H 4-NH₂ F-31 NHPr SH H 4-NH₂ F-32 NHPr SMe H 4-NH₂ F-33 NHPr SEt H 4-NH₂ F-34 NHPr S-n-Pr H 4-NH₂ F-35 NHPr S-i-Pr H 4-NH₂ F-36 NHPr S-n-Bu H 4-NH₂ F-37 NHPr S-allyl H 4-NH₂ F-38 NHPr S-propargyl H 4-NH₂ F-39 NHPr SCH₂CF₃ H 4-NH₂ F-40 NHPr SCH₂CH₂F H 4-NH₂ F-41 NH-i-Pr SH H 4-NH₂ F-42 NH-i-Pr SMe H 4-NH₂ F-43 NH-i-Pr SEt H 4-NH₂ F-44 NH-i-Pr S-n-Pr H 4-NH₂ F-45 NH-i-Pr S-i-Pr H 4-NH₂ F-46 NH-i-Pr S-n-Bu H 4-NH₂ F-47 NH-i-Pr S-allyl H 4-NH₂ F-48 NH-i-Pr S-propargyl H 4-NH₂ F-49 NH-i-Pr SCH₂CF₃ H 4-NH₂ F-50 NH-i-Pr SCH₂CH₂F H 4-NH₂ F-51 NH-allyl SH H 4-NH₂ F-52 NH-allyl SMe H 4-NH₂ F-53 NH-allyl SEt H 4-NH₂ F-54 NH-allyl S-n-Pr H 4-NH₂ F-55 NH-allyl S-i-Pr H 4-NH₂ F-56 NH-allyl S-n-Bu H 4-NH₂ F-57 NH-allyl S-allyl H 4-NH₂ F-58 NH-allyl S-propargyl H 4-NH₂ F-59 NH-allyl SCH₂CF₃ H 4-NH₂ F-60 NH-allyl SCH₂CH₂F H 4-NH₂ F-61 NH-propargyl SH H 4-NH₂ F-62 NH-propargyl SMe H 4-NH₂ F-63 NH-propargyl SEt H 4-NH₂ F-64 NH-propargyl S-n-Pr H 4-NH₂ F-65 NH-propargyl S-i-Pr H 4-NH₂ F-66 NH-propargyl S-n-Bu H 4-NH₂ F-67 NH-propargyl S-allyl H 4-NH₂ F-68 NH-propargyl S-propargyl H 4-NH₂ F-69 NH-propargyl SCH₂CF₃ H 4-NH₂ F-70 NH-propargyl SCH₂CH₂F H 4-NH₂ F-71 NHCH₂CF₃ SH H 4-NH₂ F-72 NHCH₂CF₃ SMe H 4-NH₂ F-73 NHCH₂CF₃ SEt H 4-NH₂ F-74 NHCH₂CF₃ S-n-Pr H 4-NH₂ F-75 NHCH₂CF₃ S-i-Pr H 4-NH₂ F-76 NHCH₂CF₃ S-n-Bu H 4-NH₂ F-77 NHCH₂CF₃ S-allyl H 4-NH₂ F-78 NHCH₂CF₃ S-propargyl H 4-NH₂ F-79 NHCH₂CF₃ SCH₂CF₃ H 4-NH₂ F-80 NHCH₂CF₃ SCH₂CH₂F H 4-NH₂ F-81 NHCH₂CH₂F SH H 4-NH₂ F-82 NHCH₂CH₂F SMe H 4-NH₂ F-83 NHCH₂CH₂F SEt H 4-NH₂ F-84 NHCH₂CH₂F S-n-Pr H 4-NH₂ F-85 NHCH₂CH₂F S-i-Pr H 4-NH₂ F-86 NHCH₂CH₂F S-n-Bu H 4-NH₂ F-87 NHCH₂CH₂F S-allyl H 4-NH₂ F-88 NHCH₂CH₂F S-propargyl H 4-NH₂ F-89 NHCH₂CH₂F SCH₂CF₃ H 4-NH₂ F-90 NHCH₂CH₂F SCH₂CH₂F H 4-NH₂ F-91 NH-n-Bu SH H 4-NH₂ F-92 NH-n-Bu SMe H 4-NH₂ F-93 NH-n-Bu SEt H 4-NH₂ F-94 NH-n-Bu S-n-Pr H 4-NH₂ F-95 NH-n-Bu S-i-Pr H 4-NH₂ F-96 NH-n-Bu S-n-Bu H 4-NH₂ F-97 NH-n-Bu S-allyl H 4-NH₂ F-98 NH-n-Bu S-propargyl H 4-NH₂ F-99 NH-n-Bu SCH₂CF₃ H 4-NH₂ F-100 NH-n-Bu SCH₂CH₂F H 4-NH₂

[0392] TABLE 26 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ F-101 NH₂ SH H 4-NO₂ F-102 NH₂ SMe H 4-NO₂ F-103 NH₂ SEt H 4-NO₂ F-104 NH₂ S-n-Pr H 4-NO₂ F-105 NH₂ S-i-Pr H 4-NO₂ F-106 NH₂ S-n-Bu H 4-NO₂ F-107 NH₂ S-allyl H 4-NO₂ F-108 NH₂ S-propargyl H 4-NO₂ F-109 NH₂ SCH₂CF₃ H 4-NO₂ F-110 NH₂ SCH₂CH₂F H 4-NO₂ F-111 NHMe SH H 4-NO₂ F-112 NHMe SMe H 4-NO₂ F-113 NHMe SEt H 4-NO₂ F-114 NHMe S-n-Pr H 4-NO₂ F-115 NHMe S-i-Pr H 4-NO₂ F-116 NHMe S-n-Bu H 4-NO₂ F-117 NHMe S-allyl H 4-NO₂ F-118 NHMe S-propargyl H 4-NO₂ F-119 NHMe SCH₂CF₃ H 4-NO₂ F-120 NHMe SCH₂CH₂F H 4-NO₂ F-121 NHEt SH H 4-NO₂ F-122 NHEt SMe H 4-NO₂ F-123 NHEt SEt H 4-NO₂ F-124 NHEt S-n-Pr H 4-NO₂ F-125 NHEt S-i-Pr H 4-NO₂ F-126 NHEt S-n-Bu H 4-NO₂ F-127 NHEt S-allyl H 4-NO₂ F-128 NHEt S-propargyl H 4-NO₂ F-129 NHEt SCH₂CF₃ H 4-NO₂ F-130 NHEt SCH₂CH₂F H 4-NO₂ F-131 NHPr SH H 4-NO₂ F-132 NHPr SMe H 4-NO₂ F-133 NHPr SEt H 4-NO₂ F-134 NHPr S-n-Pr H 4-NO₂ F-135 NHPr S-i-Pr H 4-NO₂ F-136 NHPr S-n-Bu H 4-NO₂ F-137 NHPr S-allyl H 4-NO₂ F-138 NHPr S-propargyl H 4-NO₂ F-139 NHPr SCH₂CF₃ H 4-NO₂ F-140 NHPr SCH₂CH₂F H 4-NO₂ F-141 NH-i-Pr SH H 4-NO₂ F-142 NH-i-Pr SMe H 4-NO₂ F-143 NH-i-Pr SEt H 4-NO₂ F-144 NH-i-Pr S-n-Pr H 4-NO₂ F-145 NH-i-Pr S-i-Pr H 4-NO₂ F-146 NH-i-Pr S-n-Bu H 4-NO₂ F-147 NH-i-Pr S-allyl H 4-NO₂ F-148 NH-i-Pr S-propargyl H 4-NO₂ F-149 NH-i-Pr SCH₂CF₃ H 4-NO₂ F-150 NH-i-Pr SCH₂CH₂F H 4-NO₂ F-151 NH-allyl SH H 4-NO₂ F-152 NH-allyl SMe H 4-NO₂ F-153 NH-allyl SEt H 4-NO₂ F-154 NH-allyl S-n-Pr H 4-NO₂ F-155 NH-allyl S-i-Pr H 4-NO₂ F-156 NH-allyl S-n-Bu H 4-NO₂ F-157 NH-allyl S-allyl H 4-NO₂ F-158 NH-allyl S-propargyl H 4-NO₂ F-159 NH-allyl SCH₂CF₃ H 4-NO₂ F-160 NH-allyl SCH₂CH₂F H 4-NO₂ F-161 NH-propargyl SH H 4-NO₂ F-162 NH-propargyl SMe H 4-NO₂ F-163 NH-propargyl SEt H 4-NO₂ F-164 NH-propargyl S-n-Pr H 4-NO₂ F-165 NH-propargyl S-i-Pr H 4-NO₂ F-166 NH-propargyl S-n-Bu H 4-NO₂ F-167 NH-propargyl S-allyl H 4-NO₂ F-168 NH-propargyl S-propargyl H 4-NO₂ F-169 NH-propargyl SCH₂CF₃ H 4-NO₂ F-170 NH-propargyl SCH₂CH₂F H 4-NO₂ F-171 NHCH₂CF₃ SH H 4-NO₂ F-172 NHCH₂CF₃ SMe H 4-NO₂ F-173 NHCH₂CF₃ SEt H 4-NO₂ F-174 NHCH₂CF₃ S-n-Pr H 4-NO₂ F-175 NHCH₂CF₃ S-i-Pr H 4-NO₂ F-176 NHCH₂CF₃ S-n-Bu H 4-NO₂ F-177 NHCH₂CF₃ S-allyl H 4-NO₂ F-178 NHCH₂CF₃ S-propargyl H 4-NO₂ F-179 NHCH₂CF₃ SCH₂CF₃ H 4-NO₂ F-180 NHCH₂CF₃ SCH₂CH₂F H 4-NO₂ F-181 NHCH₂CH₂F SH H 4-NO₂ F-182 NHCH₂CH₂F SMe H 4-NO₂ F-183 NHCH₂CH₂F SEt H 4-NO₂ F-184 NHCH₂CH₂F S-n-Pr H 4-NO₂ F-185 NHCH₂CH₂F S-i-Pr H 4-NO₂ F-186 NHCH₂CH₂F S-n-Bu H 4-NO₂ F-187 NHCH₂CH₂F S-allyl H 4-NO₂ F-188 NHCH₂CH₂F S-propargyl H 4-NO₂ F-189 NHCH₂CH₂F SCH₂CF₃ H 4-NO₂ F-190 NHCH₂CH₂F SCH₂CH₂F H 4-NO₂ F-191 NH-n-Bu SH H 4-NO₂ F-192 NH-n-Bu SMe H 4-NO₂ F-193 NH-n-Bu SEt H 4-NO₂ F-194 NH-n-Bu S-n-Pr H 4-NO₂ F-195 NH-n-Bu S-i-Pr H 4-NO₂ F-196 NH-n-Bu S-n-Bu H 4-NO₂ F-197 NH-n-Bu S-allyl H 4-NO₂ F-198 NH-n-Bu S-propargyl H 4-NO₂ F-199 NH-n-Bu SCH₂CF₃ H 4-NO₂ F-200 NH-n-Bu SCH₂CH₂F H 4-NO₂

[0393] TABLE 27 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ F-201 NH₂ SH Me 4-NH₂ F-202 NH₂ SMe Me 4-NH₂ F-203 NH₂ SEt Me 4-NH₂ F-204 NH₂ S-n-Pr Me 4-NH₂ F-205 NH₂ S-i-Pr Me 4-NH₂ F-206 NH₂ S-n-Bu Me 4-NH₂ F-207 NH₂ S-allyl Me 4-NH₂ F-208 NH₂ S-propargyl Me 4-NH₂ F-209 NH₂ SCH₂CF₃ Me 4-NH₂ F-210 NH₂ SCH₂CH₂F Me 4-NH₂ F-211 NHMe SH Me 4-NH₂ F-212 NHMe SMe Me 4-NH₂ F-213 NHMe SEt Me 4-NH₂ F-214 NHMe S-n-Pr Me 4-NH₂ F-215 NHMe S-i-Pr Me 4-NH₂ F-216 NHMe S-n-Bu Me 4-NH₂ F-217 NHMe S-allyl Me 4-NH₂ F-218 NHMe S-propargyl Me 4-NH₂ F-219 NHMe SCH₂CF₃ Me 4-NH₂ F-220 NHMe SCH₂CH₂F Me 4-NH₂ F-221 NHEt SH Me 4-NH₂ F-222 NHEt SMe Me 4-NH₂ F-223 NHEt SEt Me 4-NH₂ F-224 NHEt S-n-Pr Me 4-NH₂ F-225 NHEt S-i-Pr Me 4-NH₂ F-226 NHEt S-n-Bu Me 4-NH₂ F-227 NHEt S-allyl Me 4-NH₂ F-228 NHEt S-propargyl Me 4-NH₂ F-229 NHEt SCH₂CF₃ Me 4-NH₂ F-230 NHEt SCH₂CH₂F Me 4-NH₂ F-231 NHPr SH Me 4-NH₂ F-232 NHPr SMe Me 4-NH₂ F-233 NHPr SEt Me 4-NH₂ F-234 NHPr S-n-Pr Me 4-NH₂ F-235 NHPr S-i-Pr Me 4-NH₂ F-236 NHPr S-n-Bu Me 4-NH₂ F-237 NHPr S-allyl Me 4-NH₂ F-238 NHPr S-propargyl Me 4-NH₂ F-239 NHPr SCH₂CF₃ Me 4-NH₂ F-240 NHPr SCH₂CH₂F Me 4-NH₂ F-241 NH-i-Pr SH Me 4-NH₂ F-242 NH-i-Pr SMe Me 4-NH₂ F-243 NH-i-Pr SEt Me 4-NH₂ F-244 NH-i-Pr S-n-Pr Me 4-NH₂ F-245 NH-i-Pr S-i-Pr Me 4-NH₂ F-246 NH-i-Pr S-n-Bu Me 4-NH₂ F-247 NH-i-Pr S-allyl Me 4-NH₂ F-248 NH-i-Pr S-propargyl Me 4-NH₂ F-249 NH-i-Pr SCH₂CF₃ Me 4-NH₂ F-250 NH-i-Pr SCH₂CH₂F Me 4-NH₂ F-251 NH-allyl SH Me 4-NH₂ F-252 NH-allyl SMe Me 4-NH₂ F-253 NH-allyl SEt Me 4-NH₂ F-254 NH-allyl S-n-Pr Me 4-NH₂ F-255 NH-allyl S-i-Pr Me 4-NH₂ F-256 NH-allyl S-n-Bu Me 4-NH₂ F-257 NH-allyl S-allyl Me 4-NH₂ F-258 NH-allyl S-propargyl Me 4-NH₂ F-259 NH-allyl SCH₂CF₃ Me 4-NH₂ F-260 NH-allyl SCH₂CH₂F Me 4-NH₂ F-261 NH-propargyl SH Me 4-NH₂ F-262 NH-propargyl SMe Me 4-NH₂ F-263 NH-propargyl SEt Me 4-NH₂ F-264 NH-propargyl S-n-Pr Me 4-NH₂ F-265 NH-propargyl S-i-Pr Me 4-NH₂ F-266 NH-propargyl S-n-Bu Me 4-NH₂ F-267 NH-propargyl S-allyl Me 4-NH₂ F-268 NH-propargyl S-propargyl Me 4-NH₂ F-269 NH-propargyl SCH₂CF₃ Me 4-NH₂ F-270 NH-propargyl SCH₂CH₂F Me 4-NH₂ F-271 NHCH₂CF₃ SH Me 4-NH₂ F-272 NHCH₂CF₃ SMe Me 4-NH₂ F-273 NHCH₂CF₃ SEt Me 4-NH₂ F-274 NHCH₂CF₃ S-n-Pr Me 4-NH₂ F-275 NHCH₂CF₃ S-i-Pr Me 4-NH₂ F-276 NHCH₂CF₃ S-n-Bu Me 4-NH₂ F-277 NHCH₂CF₃ S-allyl Me 4-NH₂ F-278 NHCH₂CF₃ S-propargyl Me 4-NH₂ F-279 NHCH₂CF₃ SCH₂CF₃ Me 4-NH₂ F-280 NHCH₂CF₃ SCH₂CH₂F Me 4-NH₂ F-281 NHCH₂CH₂F SH Me 4-NH₂ F-282 NHCH₂CH₂F SMe Me 4-NH₂ F-283 NHCH₂CH₂F SEt Me 4-NH₂ F-284 NHCH₂CH₂F S-n-Pr Me 4-NH₂ F-285 NHCH₂CH₂F S-i-Pr Me 4-NH₂ F-286 NHCH₂CH₂F S-n-Bu Me 4-NH₂ F-287 NHCH₂CH₂F S-allyl Me 4-NH₂ F-288 NHCH₂CH₂F S-propargyl Me 4-NH₂ F-289 NHCH₂CH₂F SCH₂CF₃ Me 4-NH₂ F-290 NHCH₂CH₂F SCH₂CH₂F Me 4-NH₂ F-291 NH-n-Bu SH Me 4-NH₂ F-292 NH-n-Bu SMe Me 4-NH₂ F-293 NH-n-Bu SEt Me 4-NH₂ F-294 NH-n-Bu S-n-Pr Me 4-NH₂ F-295 NH-n-Bu S-i-Pr Me 4-NH₂ F-296 NH-n-Bu S-n-Bu Me 4-NH₂ F-297 NH-n-Bu S-allyl Me 4-NH₂ F-298 NH-n-Bu S-propargyl Me 4-NH₂ F-299 NH-n-Bu SCH₂CF₃ Me 4-NH₂ F-300 NH-n-Bu SCH₂CH₂F Me 4-NH₂

[0394] TABLE 28 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ F-301 NH₂ SH Me 4-NO₂ F-302 NH₂ SMe Me 4-NO₂ F-303 NH₂ SEt Me 4-NO₂ F-304 NH₂ S-n-Pr Me 4-NO₂ F-305 NH₂ S-i-Pr Me 4-NO₂ F-306 NH₂ S-n-Bu Me 4-NO₂ F-307 NH₂ S-allyl Me 4-NO₂ F-308 NH₂ S-propargyl Me 4-NO₂ F-309 NH₂ SCH₂CF₃ Me 4-NO₂ F-310 NH₂ SCH₂CH₂F Me 4-NO₂ F-311 NHMe SH Me 4-NO₂ F-312 NHMe SMe Me 4-NO₂ F-313 NHMe SEt Me 4-NO₂ F-314 NHMe S-n-Pr Me 4-NO₂ F-315 NHMe S-i-Pr Me 4-NO₂ F-316 NHMe S-n-Bu Me 4-NO₂ F-317 NHMe S-allyl Me 4-NO₂ F-318 NHMe S-propargyl Me 4-NO₂ F-319 NHMe SCH₂CF₃ Me 4-NO₂ F-320 NHMe SCH₂CH₂F Me 4-NO₂ F-321 NHEt SH Me 4-NO₂ F-322 NHEt SMe Me 4-OMe F-323 NHEt SEt Me 4-Cl F-324 NHEt S-n-Pr Me 4-NO₂ F-325 NHEt S-i-Pr Me 4-NO₂ F-326 NHEt S-n-Bu Me 4-NO₂ F-327 NHEt S-allyl Me 4-NO₂ F-328 NHEt S-propargyl Me 4-NO₂ F-329 NHEt SCH₂CF₃ Me 4-NO₂ F-330 NHEt SCH₂CH₂F Me 4-NO₂ F-331 NHPr SH Me 4-NO₂ F-332 NHPr SMe Me 4-NO₂ F-333 NHPr SEt Me 4-NO₂ F-334 NHPr S-n-Pr Me 4-NO₂ F-335 NHPr S-i-Pr Me 4-NO₂ F-336 NHPr S-n-Bu Me 4-NO₂ F-337 NHPr S-allyl Me 4-NO₂ F-338 NHPr S-propargyl Me 4-NO₂ F-339 NHPr SCH₂CF₃ Me 4-NO₂ F-340 NHPr SCH₂CH₂F Me 4-NO₂ F-341 NH-i-Pr SH Me 4-NO₂ F-342 NH-i-Pr SMe Me 4-NO₂ F-343 NH-i-Pr SEt Me 4-NO₂ F-344 NH-i-Pr S-n-Pr Me 4-NO₂ F-345 NH-i-Pr S-i-Pr Me 4-NO₂ F-346 NH-i-Pr S-n-Bu Me 4-NO₂ F-347 NH-i-Pr S-allyl Me 4-NO₂ F-348 NH-i-Pr S-propargyl Me 4-NO₂ F-349 NH-i-Pr SCH₂CF₃ Me 4-NO₂ F-350 NH-i-Pr SCH₂CH₂F Me 4-NO₂ F-351 NH-allyl SH Me 4-NO₂ F-352 NH-allyl SMe Me 4-NO₂ F-353 NH-allyl SEt Me 4-NO₂ F-354 NH-allyl S-n-Pr Me 4-NO₂ F-355 NH-allyl S-i-Pr Me 4-NO₂ F-356 NH-allyl S-n-Bu Me 4-NO₂ F-357 NH-allyl S-allyl Me 4-NO₂ F-358 NH-allyl S-propargyl Me 4-NO₂ F-359 NH-allyl SCH₂CF₃ Me 4-NO₂ F-360 NH-allyl SCH₂CH₂F Me 4-NO₂ F-361 NH-propargyl SH Me 4-NO₂ F-362 NH-propargyl SMe Me 4-NO₂ F-363 NH-propargyl SEt Me 4-NO₂ F-364 NH-propargyl S-n-Pr Me 4-NO₂ F-365 NH-propargyl S-i-Pr Me 4-NO₂ F-366 NH-propargyl S-n-Bu Me 4-NO₂ F-367 NH-propargyl S-allyl Me 4-NO₂ F-368 NH-propargyl S-propargyl Me 4-NO₂ F-369 NH-propargyl SCH₂CF₃ Me 4-NO₂ F-370 NH-propargyl SCH₂CH₂F Me 4-NO₂ F-371 NHCH₂CF₃ SH Me 4-NO₂ F-372 NHCH₂CF₃ SMe Me 4-NO₂ F-373 NHCH₂CF₃ SEt Me 4-NO₂ F-374 NHCH₂CF₃ S-n-Pr Me 4-NO₂ F-375 NHCH₂CF₃ S-i-Pr Me 4-NO₂ F-376 NHCH₂CF₃ S-n-Bu Me 4-NO₂ F-377 NHCH₂CF₃ S-allyl Me 4-NO₂ F-378 NHCH₂CF₃ S-propargyl Me 4-NO₂ F-379 NHCH₂CF₃ SCH₂CF₃ Me 4-NO₂ F-380 NHCH₂CF₃ SCH₂CH₂F Me 4-NO₂ F-381 NHCH₂CH₂F SH Me 4-NO₂ F-382 NHCH₂CH₂F SMe Me 4-NO₂ F-383 NHCH₂CH₂F SEt Me 4-NO₂ F-384 NHCH₂CH₂F S-n-Pr Me 4-NO₂ F-385 NHCH₂CH₂F S-i-Pr Me 4-NO₂ F-386 NHCH₂CH₂F S-n-Bu Me 4-NO₂ F-387 NHCH₂CH₂F S-allyl Me 4-NO₂ F-388 NHCH₂CH₂F S-propargyl Me 4-NO₂ F-389 NHCH₂CH₂F SCH₂CF₃ Me 4-NO₂ F-390 NHCH₂CH₂F SCH₂CH₂F Me 4-NO₂ F-391 NH-n-Bu SH Me 4-NO₂ F-392 NH-n-Bu SMe Me 4-NO₂ F-393 NH-n-Bu SEt Me 4-NO₂ F-394 NH-n-Bu S-n-Pr Me 4-NO₂ F-395 NH-n-Bu S-i-Pr Me 4-NO₂ F-396 NH-n-Bu S-n-Bu Me 4-NO₂ F-397 NH-n-Bu S-allyl Me 4-NO₂ F-398 NH-n-Bu S-propargyl Me 4-NO₂ F-399 NH-n-Bu SCH₂CF₃ Me 4-NO₂ F-400 NH-n-Bu SCH₂CH₂F Me 4-NO₂

[0395] TABLE 29 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ F-401 NH₂ NH₂ Me 4-NO₂ F-402 NH₂ NHMe Me 4-NO₂ F-403 NH₂ NHEt Me 4-NO₂ F-404 NH₂ NHPr Me 4-NO₂ F-405 NH₂ NH-i-Pr Me 4-NO₂ F-406 NH₂ NH-n-Bu Me 4-NO₂ F-407 NH₂ NH-allyl Me 4-NO₂ F-408 NH₂ NH-propargyl Me 4-NO₂ F-409 NH₂ NHCH₂CF₃ Me 4-NO₂ F-410 NH₂ NHCH₂CH₂F Me 4-NO₂ F-411 NHMe NHMe Me 4-NO₂ F-412 NHMe NHEt Me 4-NO₂ F-413 NHMe NHPr Me 4-NO₂ F-414 NHMe NH-i-Pr Me 4-NO₂ F-415 NHMe NH-n-Bu Me 4-NO₂ F-416 NHMe NH-allyl Me 4-NO₂ F-417 NHMe NH-propargyl Me 4-NO₂ F-418 NHMe NHCH₂CF₃ Me 4-NO₂ F-419 NHMe NHCH₂CH₂F Me 4-NO₂ F-420 NHEt NHEt Me 4-Cl F-421 NHEt NHPr Me 4-NO₂ F-422 NHEt NH-i-Pr Me 4-NO₂ F-423 NHEt NH-n-Bu Me 4-NO₂ F-424 NHEt NH-allyl Me 4-NO₂ F-425 NHEt NH-propargyl Me 4-NO₂ F-426 NHEt NHCH₂CF₃ Me 4-NO₂ F-427 NHEt NHCH₂CH₂F Me 4-NO₂ F-428 NHPr NHPr Me 4-NO₂ F-429 NHPr NH-i-Pr Me 4-NO₂ F-430 NHPr NH-n-Bu Me 4-NO₂ F-431 NHPr NH-allyl Me 4-NO₂ F-432 NHPr NH-propargyl Me 4-NO₂ F-433 NHPr NHCH₂CF₃ Me 4-NO₂ F-434 NHPr NHCH₂CH₂F Me 4-NO₂ F-435 NH-i-Pr NH-i-Pr Me 4-NO₂ F-436 NH-i-Pr NH-n-Bu Me 4-NO₂ F-437 NH-i-Pr NH-allyl Me 4-NO₂ F-438 NH-i-Pr NH-propargyl Me 4-NO₂ F-439 NH-i-Pr NHCH₂CF₃ Me 4-NO₂ F-440 NH-i-Pr NHCH₂CH₂F Me 4-NO₂ F-441 NH-n-Bu NH-n-Bu Me 4-NO₂ F-442 NH-n-Bu NH-allyl Me 4-NO₂ F-443 NH-n-Bu NH-propargyl Me 4-NO₂ F-444 NH-n-Bu NHCH₂CF₃ Me 4-NO₂ F-445 NH-n-Bu NHCH₂CH₂F Me 4-NO₂ F-446 NH-allyl NH-allyl Me 4-NO₂ F-447 NH-allyl NH-propargyl Me 4-NO₂ F-448 NH-allyl NHCH₂CF₃ Me 4-NO₂ F-449 NH-allyl NHCH₂CH₂F Me 4-NO₂ F-450 NH-propargyl NH-propargyl Me 4-NO₂ F-451 NH-propargyl NHCH₂CF₃ Me 4-NO₂ F-452 NH-propargyl NHCH₂CH₂F Me 4-NO₂ F-453 NHCH₂CF₃ NHCH₂CF₃ Me 4-NO₂ F-454 NHCH₂CF₃ NHCH₂CH₂F Me 4-NO₂ F-455 NHCH₂CH₂F NHCH₂CH₂F Me 4-NO₂ F-456 NHOMe NH₂ Me 4-NO₂ F-457 NHOMe NHMe Me 4-NO₂ F-458 NHOMe NHEt Me 4-NO₂ F-459 NHOMe NHPr Me 4-NO₂ F-460 NHOMe NH-i-Pr Me 4-NO₂ F-461 NHOMe NH-n-Bu Me 4-NO₂ F-462 NHOMe NH-allyl Me 4-NO₂ F-463 NHOMe NH-propargyl Me 4-NO₂ F-464 NHOMe NHCH₂CF₃ Me 4-NO₂ F-465 NHOMe NHCH₂CH₂F Me 4-NO₂ F-466 NHOEt NH₂ Me 4-NO₂ F-467 NHOEt NHMe Me 4-NO₂ F-468 NHOEt NHEt Me 4-NO₂ F-469 NHOEt NHPr Me 4-NO₂ F-470 NHOEt NH-i-Pr Me 4-NO₂ F-471 NHOEt NH-n-Bu Me 4-NO₂ F-472 NHOEt NH-allyl Me 4-NO₂ F-473 NHOEt NH-propargyl Me 4-NO₂ F-474 NHOEt NHCH₂CF₃ Me 4-NO₂ F-475 NHOEt NHCH₂CH₂F Me 4-NO₂ F-476 NHNMe₂ NH₂ Me 4-NO₂ F-477 NHNMe₂ NHMe Me 4-NO₂ F-478 NHNMe₂ NHEt Me 4-NO₂ F-479 NHNMe₂ NHPr Me 4-NO₂ F-480 NHNMe₂ NH-i-Pr Me 4-NO₂ F-481 NHNMe₂ NH-n-Bu Me 4-NO₂ F-482 NHNMe₂ NH-allyl Me 4-NO₂ F-483 NHNMe₂ NH-propargyl Me 4-NO₂ F-484 NHNMe₂ NHCH₂CF₃ Me 4-NO₂ F-485 NHNMe₂ NHCH₂CH₂F Me 4-NO₂ F-486 NHNH₂ NH₂ Me 4-NO₂ F-487 NHNH₂ NHMe Me 4-NO₂ F-488 NHNH₂ NHEt Me 4-NO₂ F-489 NHNH₂ NHPr Me 4-NO₂ F-490 NHNH₂ NH-i-Pr Me 4-NO₂ F-491 NHNH₂ NH-n-Bu Me 4-NO₂ F-492 NHNH₂ NH-allyl Me 4-NO₂ F-493 NHNH₂ NH-propargyl Me 4-NO₂ F-494 NHNH₂ NHCH₂CF₃ Me 4-NO₂ F-495 NHNH₂ NHCH₂CH₂F Me 4-NO₂ F-496 NHNHMe NHMe Me 4-NO₂ F-497 NHNHMe NHEt Me 4-NO₂ F-498 NHNHMe NHPr Me 4-NO₂ F-499 NHNHMe NH-i-Pr Me 4-NO₂ F-500 NHNHMe NHCH₂CF₃ Me 4-NO₂

[0396] TABLE 30 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ F-501 NH₂ NH₂ H 4-NO₂ F-502 NH₂ NHMe H 4-NO₂ F-503 NH₂ NHEt H 4-NO₂ F-504 NH₂ NHPr H 4-NO₂ F-505 NH₂ NH-i-Pr H 4-NO₂ F-506 NH₂ NH-n-Bu H 4-NO₂ F-507 NH₂ NH-allyl H 4-NO₂ F-508 NH₂ NH-propargyl H 4-NO₂ F-509 NH₂ NHCH₂CF₃ H 4-NO₂ F-510 NH₂ NHCH₂CH₂F H 4-NO₂ F-511 NHMe NHMe H 4-NO₂ F-512 NHMe NHEt H 4-NO₂ F-513 NHMe NHPr H 4-NO₂ F-514 NHMe NH-i-Pr H 4-NO₂ F-515 NHMe NH-n-Bu H 4-NO₂ F-516 NHMe NH-allyl H 4-NO₂ F-517 NHMe NH-propargyl H 4-NO₂ F-518 NHMe NHCH₂CF₃ H 4-NO₂ F-519 NHMe NHCH₂CH₂F H 4-NO₂ F-520 NHEt NHEt H 4-NO₂ F-521 NHEt NHPr H 4-NO₂ F-522 NHEt NH-i-Pr H 4-NO₂ F-523 NHEt NH-n-Bu H 4-NO₂ F-524 NHEt NH-allyl H 4-NO₂ F-525 NHEt NH-propargyl H 4-NO₂ F-526 NHEt NHCH₂CF₃ H 4-NO₂ F-527 NHEt NHCH₂CH₂F H 4-NO₂ F-528 NHPr NHPr H 4-NO₂ F-529 NHPr NH-i-Pr H 4-NO₂ F-530 NHPr NH-n-Bu H 4-NO₂ F-531 NHPr NH-allyl H 4-NO₂ F-532 NHPr NH-propargyl H 4-NO₂ F-533 NHPr NHCH₂CF₃ H 4-NO₂ F-534 NHPr NHCH₂CH₂F H 4-NO₂ F-535 NH-i-Pr NH-i-Pr H 4-NO₂ F-536 NH-i-Pr NH-n-Bu H 4-NO₂ F-537 NH-i-Pr NH-allyl H 4-NO₂ F-538 NH-i-Pr NH-propargyl H 4-NO₂ F-539 NH-i-Pr NHCH₂CF₃ H 4-NO₂ F-540 NH-i-Pr NHCH₂CH₂F H 4-NO₂ F-541 NH-n-Bu NH-n-Bu H 4-NO₂ F-542 NH-n-Bu NH-allyl H 4-NO₂ F-543 NH-n-Bu NH-propargyl H 4-NO₂ F-544 NH-n-Bu NHCH₂CF₃ H 4-NO₂ F-545 NH-n-Bu NHCH₂CH₂F H 4-NO₂ F-546 NH-allyl NH-allyl H 4-NO₂ F-547 NH-allyl NH-propargyl H 4-NO₂ F-548 NH-allyl NHCH₂CF₃ H 4-NO₂ F-549 NH-allyl NHCH₂CH₂F H 4-NO₂ F-550 NH-propargyl NH-propargyl H 4-NO₂ F-551 NH-propargyl NHCH₂CF₃ H 4-NO₂ F-552 NH-propargyl NHCH₂CH₂F H 4-NO₂ F-553 NHCH₂CF₃ NHCH₂CF₃ H 4-NO₂ F-554 NHCH₂CF₃ NHCH₂CH₂F H 4-NO₂ F-555 NHCH₂CH₂F NHCH₂CH₂F H 4-NO₂ F-556 NHOMe NH₂ H 4-NO₂ F-557 NHOMe NHMe H 4-NO₂ F-558 NHOMe NHEt H 4-NO₂ F-559 NHOMe NHPr H 4-NO₂ F-560 NHOMe NH-i-Pr H 4-NO₂ F-561 NHOMe NH-n-Bu H 4-NO₂ F-562 NHOMe NH-allyl H 4-NO₂ F-563 NHOMe NH-propargyl H 4-NO₂ F-564 NHOMe NHCH₂CF₃ H 4-NO₂ F-565 NHOMe NHCH₂CH₂F H 4-NO₂ F-566 NHOEt NH₂ H 4-NO₂ F-567 NHOEt NHMe H 4-NO₂ F-568 NHOEt NHEt H 4-NO₂ F-569 NHOEt NHPr H 4-NO₂ F-570 NHOEt NH-i-Pr H 4-NO₂ F-571 NHOEt NH-n-Bu H 4-NO₂ F-572 NHOEt NH-allyl H 4-NO₂ F-573 NHOEt NH-propargyl H 4-NO₂ F-574 NHOEt NHCH₂CF₃ H 4-NO₂ F-575 NHOEt NHCH₂CH₂F H 4-NO₂ F-576 NHNMe₂ NH₂ H 4-NO₂ F-577 NHNMe₂ NHMe H 4-NO₂ F-578 NHNMe₂ NHEt H 4-NO₂ F-579 NHNMe₂ NHPr H 4-NO₂ F-580 NHNMe₂ NH-i-Pr H 4-NO₂ F-581 NHNMe₂ NH-n-Bu H 4-NO₂ F-582 NHNMe₂ NH-allyl H 4-NO₂ F-583 NHNMe₂ NH-propargyl H 4-NO₂ F-584 NHNMe₂ NHCH₂CF₃ H 4-NO₂ F-585 NHNMe₂ NHCH₂CH₂F H 4-NO₂ F-586 NHNH₂ NH₂ H 4-NO₂ F-587 NHNH₂ NHMe H 4-NO₂ F-588 NHNH₂ NHEt H 4-NO₂ F-589 NHNH₂ NHPr H 4-NO₂ F-590 NHNH₂ NH-i-Pr H 4-NO₂ F-591 NHNH₂ NH-n-Bu H 4-NO₂ F-592 NHNH₂ NH-allyl H 4-NO₂ F-593 NHNH₂ NH-propargyl H 4-NO₂ F-594 NHNH₂ NHCH₂CF₃ H 4-NO₂ F-595 NHNH₂ NHCH₂CH₂F H 4-NO₂ F-596 NHNHMe NHMe H 4-NO₂ F-597 NHNHMe NHEt H 4-NO₂ F-598 NHNHMe NHPr H 4-NO₂ F-599 NHNHMe NH-i-Pr H 4-NO₂ F-600 NHNHMe NHCH₂CF₃ H 4-NO₂

[0397] TABLE 31 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ F-601 NH₂ NH₂ Me 4-NH₂ F-602 NH₂ NHMe Me 4-NH₂ F-603 NH₂ NHEt Me 4-NH₂ F-604 NH₂ NHPr Me 4-NH₂ F-605 NH₂ NH-i-Pr Me 4-NH₂ F-606 NH₂ NH-n-Bu Me 4-NH₂ F-607 NH₂ NH-allyl Me 4-NH₂ F-608 NH₂ NH-propargyl Me 4-NH₂ F-609 NH₂ NHCH₂CF₃ Me 4-NH₂ F-610 NH₂ NHCH₂CH₂F Me 4-NH₂ F-611 NHMe NHMe Me 4-NH₂ F-612 NHMe NHEt Me 4-NH₂ F-613 NHMe NHPr Me 4-NH₂ F-614 NHMe NH-i-Pr Me 4-NH₂ F-615 NHMe NH-n-Bu Me 4-NH₂ F-616 NHMe NH-allyl Me 4-NH₂ F-617 NHMe NH-propargyl Me 4-NH₂ F-618 NHMe NHCH₂CF₃ Me 4-NH₂ F-619 NHMe NHCH₂CH₂F Me 4-NH₂ F-620 NHEt NHEt Me 4-NH₂ F-621 NHEt NHPr Me 4-NH₂ F-622 NHEt NH-i-Pr Me 4-NH₂ F-623 NHEt NH-n-Bu Me 4-NH₂ F-624 NHEt NH-allyl Me 4-NH₂ F-625 NHEt NH-propargyl Me 4-NH₂ F-626 NHEt NHCH₂CF₃ Me 4-NH₂ F-627 NHEt NHCH₂CH₂F Me 4-NH₂ F-628 NHPr NHPr Me 4-NH₂ F-629 NHPr NH-i-Pr Me 4-NH₂ F-630 NHPr NH-n-Bu Me 4-NH₂ F-631 NHPr NH-allyl Me 4-NH₂ F-632 NHPr NH-propargyl Me 4-NH₂ F-633 NHPr NHCH₂CF₃ Me 4-NH₂ F-634 NHPr NHCH₂CH₂F Me 4-NH₂ F-635 NH-i-Pr NH-i-Pr Me 4-NH₂ F-636 NH-i-Pr NH-n-Bu Me 4-NH₂ F-637 NH-i-Pr NH-allyl Me 4-NH₂ F-638 NH-i-Pr NH-propargyl Me 4-NH₂ F-639 NH-i-Pr NHCH₂CF₃ Me 4-NH₂ F-640 NH-i-Pr NHCH₂CH₂F Me 4-NH₂ F-641 NH-n-Bu NH-n-Bu Me 4-NH₂ F-642 NH-n-Bu NH-allyl Me 4-NH₂ F-643 NH-n-Bu NH-propargyl Me 4-NH₂ F-644 NH-n-Bu NHCH₂CF₃ Me 4-NH₂ F-645 NH-n-Bu NHCH₂CH₂F Me 4-NH₂ F-646 NH-allyl NH-allyl Me 4-NH₂ F-647 NH-allyl NH-propargyl Me 4-NH₂ F-648 NH-allyl NHCH₂CF₃ Me 4-NH₂ F-649 NH-allyl NHCH₂CH₂F Me 4-NH₂ F-650 NH-propargyl NH-propargyl Me 4-NH₂ F-651 NH-propargyl NHCH₂CF₃ Me 4-NH₂ F-652 NH-propargyl NHCH₂CH₂F Me 4-NH₂ F-653 NHCH₂CF₃ NHCH₂CF₃ Me 4-NH₂ F-654 NHCH₂CF₃ NHCH₂CH₂F Me 4-NH₂ F-655 NHCH₂CH₂F NHCH₂CH₂F Me 4-NH₂ F-656 NHOMe NH₂ Me 4-NH₂ F-657 NHOMe NHMe Me 4-NH₂ F-658 NHOMe NHEt Me 4-NH₂ F-659 NHOMe NHPr Me 4-NH₂ F-660 NHOMe NH-i-Pr Me 4-NH₂ F-661 NHOMe NH-n-Bu Me 4-NH₂ F-662 NHOMe NH-allyl Me 4-NH₂ F-663 NHOMe NH-propargyl Me 4-NH₂ F-664 NHOMe NHCH₂CF₃ Me 4-NH₂ F-665 NHOMe NHCH₂CH₂F Me 4-NH₂ F-666 NHOEt NH₂ Me 4-NH₂ F-667 NHOEt NHMe Me 4-NH₂ F-668 NHOEt NHEt Me 4-NH₂ F-669 NHOEt NHPr Me 4-NH₂ F-670 NHOEt NH-i-Pr Me 4-NH₂ F-671 NHOEt NH-n-Bu Me 4-NH₂ F-672 NHOEt NH-allyl Me 4-NH₂ F-673 NHOEt NH-propargyl Me 4-NH₂ F-674 NHOEt NHCH₂CF₃ Me 4-NH₂ F-675 NHOEt NHCH₂CH₂F Me 4-NH₂ F-676 NHNMe₂ NH₂ Me 4-NH₂ F-677 NHNMe₂ NHMe Me 4-NH₂ F-678 NHNMe₂ NHEt Me 4-NH₂ F-679 NHNMe₂ NHPr Me 4-NH₂ F-680 NHNMe₂ NH-i-Pr Me 4-NH₂ F-681 NHNMe₂ NH-n-Bu Me 4-NH₂ F-682 NHNMe₂ NH-allyl Me 4-NH₂ F-683 NHNMe₂ NH-propargyl Me 4-NH₂ F-684 NHNMe₂ NHCH₂CF₃ Me 4-NH₂ F-685 NHNMe₂ NHCH₂CH₂F Me 4-NH₂ F-686 NHNH₂ NH₂ Me 4-NH₂ F-687 NHNH₂ NHMe Me 4-NH₂ F-688 NHNH₂ NHEt Me 4-NH₂ F-689 NHNH₂ NHPr Me 4-NH₂ F-690 NHNH₂ NH-i-Pr Me 4-NH₂ F-691 NHNH₂ NH-n-Bu Me 4-NH₂ F-692 NHNH₂ NH-allyl Me 4-NH₂ F-693 NHNH₂ NH-propargyl Me 4-NH₂ F-694 NHNH₂ NHCH₂CF₃ Me 4-NH₂ F-695 NHNH₂ NHCH₂CH₂F Me 4-NH₂ F-696 NHNHMe NHMe Me 4-NH₂ F-697 NHNHMe NHEt Me 4-NH₂ F-698 NHNHMe NHPr Me 4-NH₂ F-699 NHNHMe NH-i-Pr Me 4-NH₂ F-700 NHNHMe NHCH₂CF₃ Me 4-NH₂

[0398] TABLE 32 Com- pound No. R¹⁵ R¹⁶ R¹⁷ R¹⁸ F-701 NH₂ NH₂ H 4-NH₂ F-702 NH₂ NHMe H 4-NH₂ F-703 NH₂ NHEt H 4-NH₂ F-704 NH₂ NHPr H 4-NH₂ F-705 NH₂ NH-i-Pr H 4-NH₂ F-706 NH₂ NH-n-Bu H 4-NH₂ F-707 NH₂ NH-allyl H 4-NH₂ F-708 NH₂ NH-propargyl H 4-NH₂ F-709 NH₂ NHCH₂CF₃ H 4-NH₂ F-710 NH₂ NHCH₂CH₂F H 4-NH₂ F-711 NHMe NHMe H 4-NH₂ F-712 NHMe NHEt H 4-NH₂ F-713 NHMe NHPr H 4-NH₂ F-714 NHMe NH-i-Pr H 4-NH₂ F-715 NHMe NH-n-Bu H 4-NH₂ F-716 NHMe NH-allyl H 4-NH₂ F-717 NHMe NH-propargyl H 4-NH₂ F-718 NHMe NHCH₂CF₃ H 4-NH₂ F-719 NHMe NHCH₂CH₂F H 4-NH₂ F-720 NHEt NHEt H 4-NH₂ F-721 NHEt NHPr H 4-NH₂ F-722 NHEt NH-i-Pr H 4-NH₂ F-723 NHEt NH-n-Bu H 4-NH₂ F-724 NHEt NH-allyl H 4-NH₂ F-725 NHEt NH-propargyl H 4-NH₂ F-726 NHEt NHCH₂CF₃ H 4-NH₂ F-727 NHEt NHCH₂CH₂F H 4-NH₂ F-728 NHPr NHPr H 4-NH₂ F-729 NHPr NH-i-Pr H 4-NH₂ F-730 NHPr NH-n-Bu H 4-NH₂ F-731 NHPr NH-allyl H 4-NH₂ F-732 NHPr NH-propargyl H 4-NH₂ F-733 NHPr NHCH₂CF₃ H 4-NH₂ F-734 NHPr NHCH₂CH₂F H 4-NH₂ F-735 NH-i-Pr NH-i-Pr H 4-NH₂ F-736 NH-i-Pr NH-n-Bu H 4-NH₂ F-737 NH-i-Pr NH-allyl H 4-NH₂ F-738 NH-i-Pr NH-propargyl H 4-NH₂ F-739 NH-i-Pr NHCH₂CF₃ H 4-NH₂ F-740 NH-i-Pr NHCH₂CH₂F H 4-NH₂ F-741 NH-n-Bu NH-n-Bu H 4-NH₂ F-742 NH-n-Bu NH-allyl H 4-NH₂ F-743 NH-n-Bu NH-propargyl H 4-NH₂ F-744 NH-n-Bu NHCH₂CF₃ H 4-NH₂ F-745 NH-n-Bu NHCH₂CH₂F H 4-NH₂ F-746 NH-allyl NH-allyl H 4-NH₂ F-747 NH-allyl NH-propargyl H 4-NH₂ F-748 NH-allyl NHCH₂CF₃ H 4-NH₂ F-749 NH-allyl NHCH₂CH₂F H 4-NH₂ F-750 NH-propargyl NH-propargyl H 4-NH₂ F-751 NH-propargyl NHCH₂CF₃ H 4-NH₂ F-752 NH-propargyl NHCH₂CH₂F H 4-NH₂ F-753 NHCH₂CF₃ NHCH₂CF₃ H 4-NH₂ F-754 NHCH₂CF₃ NHCH₂CH₂F H 4-NH₂ F-755 NHCH₂CH₂F NHCH₂CH₂F H 4-NH₂ F-756 NHOMe NH₂ H 4-NH₂ F-757 NHOMe NHMe H 4-NH₂ F-758 NHOMe NHEt H 4-NH₂ F-759 NHOMe NHPr H 4-NH₂ F-760 NHOMe NH-i-Pr H 4-NH₂ F-761 NHOMe NH-n-Bu H 4-NH₂ F-762 NHOMe NH-allyl H 4-NH₂ F-763 NHOMe NH-propargyl H 4-NH₂ F-764 NHOMe NHCH₂CF₃ H 4-NH₂ F-765 NHOMe NHCH₂CH₂F H 4-NH₂ F-766 NHOEt NH₂ H 4-NH₂ F-767 NHOEt NHMe H 4-NH₂ F-768 NHOEt NHEt H 4-NH₂ F-769 NHOEt NHPr H 4-NH₂ F-770 NHOEt NH-i-Pr H 4-NH₂ F-771 NHOEt NH-n-Bu H 4-NH₂ F-772 NHOEt NH-allyl H 4-NH₂ F-773 NHOEt NH-propargyl H 4-NH₂ F-774 NHOEt NHCH₂CF₃ H 4-NH₂ F-775 NHOEt NHCH₂CH₂F H 4-NH₂ F-776 NHNMe₂ NH₂ H 4-NH₂ F-777 NHNMe₂ NHMe H 4-NH₂ F-778 NHNMe₂ NHEt H 4-NH₂ F-779 NHNMe₂ NHPr H 4-NH₂ F-780 NHNMe₂ NH-i-Pr H 4-NH₂ F-781 NHNMe₂ NH-n-Bu H 4-NH₂ F-782 NHNMe₂ NH-allyl H 4-NH₂ F-783 NHNMe₂ NH-propargyl H 4-NH₂ F-784 NHNMe₂ NHCH₂CF₃ H 4-NH₂ F-785 NHNMe₂ NHCH₂CH₂F H 4-NH₂ F-786 NHNH₂ NH₂ H 4-NH₂ F-787 NHNH₂ NHMe H 4-NH₂ F-788 NHNH₂ NHEt H 4-NH₂ F-789 NHNH₂ NHPr H 4-NH₂ F-790 NHNH₂ NH-i-Pr H 4-NH₂ F-791 NHNH₂ NH-n-Bu H 4-NH₂ F-792 NHNH₂ NH-allyl H 4-NH₂ F-793 NHNH₂ NH-propargyl H 4-NH₂ F-794 NHNH₂ NHCH₂CF₃ H 4-NH₂ F-795 NHNH₂ NHCH₂CH₂F H 4-NH₂ F-796 NHNHMe NHMe H 4-NH₂ F-797 NHNHMe NHEt H 4-NH₂ F-798 NHNHMe NHPr H 4-NH₂ F-799 NHNHMe NH-i-Pr H 4-NH₂ F-800 NHNHMe NHCH₂CF₃ H 4-NH₂

Test Example 1 Inhibitory Effect Against Cellular Signaling Derived from Ras Oncogene Products

[0399] 1) Establishment of Cell Lines Used in Assay

[0400] Based on the reporter plasmid (pGV-P (Toyo Ink, Japan)), in which luciferase gene was ligated to SV40-derived minimal promoter, we constructed a plasmid designated pRRE3-luc by inserting 3 copies of chemically synthesized oligonucleotides (Sequence CAGGATATGACTCT, derived from mouse NVL-3 (M. A. Reddy et al.(1992) Mol. Endocrinol., 6, 1051)) into upstream of the promoter. v-ki-ras-transformed NIH3T3 cells (DT cells, provided by Dr. Makoto Noda (Kyoto Univ., School of medicine)) were transfected with this plasmid by liposome-mediated transfection and transfected cell lines stably incorporated and maintained each plasmid were obtained. We named pGV-P and pRRE3-transfected cell line as DT-C and DT-R, respectively and used in the assay described below.

[0401] 2) Preparation of Samples

[0402] i) All the cell lines were cultured in Dulbecco's Modified Essential Medium (DMEM: 10% Fetal Calf Serum (FCS: Hyclone, USA)) including 60 mg/ml kanamycin (Meiji Seika, Japan) in humidified incubator under condition of 5% CO₂ at 37° C.

[0403] ii) DT-C and DT-R cells were seeded at 2500 cells/well into flat-bottom 96 well multiplate (Sumitomo bakelite) and incubated for 24 hours.

[0404] iii) Test compounds were prepared as 1 mg/ml DMSO solution.

[0405] iv) The solution of test compounds were added to the culture. Tested compounds are used at the concentration from 10 mg/ml to 0.51 ng/ml with 3-fold dilution.

[0406] v) After 24 hours, the culture supernatant was completely aspirated and 20 μl of cell-lysing solution (PGC-50 (Toyo Ink, Japan)) was added before cells were dried up. In order to lyse the cells completely, multiwell plates were left at room temperature for 10 to 30 min. The plates were wrapped up and stored at −20° C. till the day of measurement.

[0407] 3) Measurement of Samples

[0408] i) Melt the samples by putting 96 well multiplate at 37° C. and add 90 μl/well 25 mM Tris (pH 7.5).

[0409] ii) Transfer 50 μl of the sample (110 μl) to the 96 well microplate (Microlite 1 (Dynatech)) for measurement.

[0410] iii) Measure the samples by the luminometer, LUMINOUS CT9000D (Dia-Yatron, Japan). We used Pickagene luminescence kit PGL2000 or LT2.0 (Toyo Ink, Japan) as enzyme substrates for luminescence measurement (50 μl/well).

[0411] 4) Judgment of the Results

[0412] i) The luciferase activity of DT-C cells and DT-R cells were plotted in the graph where the relative activity and the compound concentration were expressed as Y-axis and X-axis, respectively. We judged by the degree of dissociation between the activities of DT-C cells and DT-R cells as an index.

[0413] ii) Concretely, efficacy of the compound was expressed by two values described below.

[0414] a) Among the points of concentration tested, the minimal concentration (Minimal Active Concentration: MAC), at which the activities of DT-C cells and DT-R cells dissociated, was shown as an index of efficacy of the compound.

[0415] b) Among the points of concentration tested, the concentration which is the nearest to 50% inhibition concentration at DT-C cells (IC50-C), was shown as an index of non-specific transcription-inhibitory effect or of cytotoxicity. In case of positive compounds, 50% inhibition concentration in DT-C cells which was higher than the active concentration was expressed as IC₅₀-C.

[0416] The results of the assay were shown in table 33. TABLE 33 Compound No. MAC (μg/ml) IC50 (μg/ml) A-1 1.11 >10 A-2 1.11 >10 A-3 0.37 >10 A-4 0.37 >10 A-5 0.123 10 A-6 0.0412 10 A-7 0.123 3.33 A-8 0.123 >10 A-10 1.11 >10 A-11 0.0412 >10 A-12 0.0137 >10 A-13 0.0137 10 A-14 0.0412 >10 A-15 0.00152 >10 A-16 <0.000508 >10 A-17 0.0412 >10 A-18 0.00457 >10 A-19 0.37 >10 A-21 0.37 10 A-22 1.11 >10 A-23 3.33 >10 A-32 0.123 >10 A-33 0.0412 >10 A-34 0.0137 >10 A-35 0.0412 >10 C-1 0.0412 10 C-2 0.0137 >10

Test Example 2 In vitro Cell Growth Inhibition Test

[0417] Cells and MTT Assay

[0418] Human squamous lung cancer RERF-RC-AI, human squamous lung cancer Ma44, human lung adenocarcinoma A549, human colon cancer HT29 and human pancreas cancer PANC-1 were used. All cell lines were cultured with Eagle's Modified Essential Medium (EMEM, supplemented with 10% fetal calf serum (FCS: Hyclone, USA) and 60 μg/ml Kanamycin (Meiji-seika, Japan) at 37° C. in a humidified incubator (5% CO₂). The cells were plated in 96-well microcultureplate. Twenty-four hours later, compound were added at the concentration from 10 μg/ml to 0.1 ng/ml with 2-fold dilution. MTT assay was performed 4 days later and IC₅₀ values were determined. The results were shown in Table 34 in terms of concentration at ng/ml. TABLE 34 Compound No. A549 HT-29 Ma44 PANC-1 RERF-LC-AI H460 A-1 0.9 45 120 46 A-2 34 140 370 160 A-3 63 52 56 51 46 A-4 38 23 51 26 30 A-5 70 48.4 44.6 66.5 33 89 A-6 25.6 24.4 18.2 14.8 15 25.6 A-7 2.1 3.6 1.6 0.6 1.3 3.8 A-8 9.3 41.4 34.1 37.1 27.8 6.8 A-10 80 A-11 14 6.7 77 6.4 A-12 8 6.3 9.5 9.1 5.7 11.5 A-13 15 8.9 30 7.7 A-14 12 11 32 9.8 12 A-15 11.1 10.3 12.7 12.4 6.5 15.3 A-16 14.6 8.1 13.6 6.5 7.3 10.7 A-17 17.4 15 24.1 10.7 13.2 15 A-18 51.4 0.4 0.4 0.4 0.4 27.5 A-19 83 A-21 22 A-22 42 A-32 64 31 42 34 31 A-33 23 6.6 9.1 8.6 9.3 A-34 21 4.6 9.1 7.5 13 A-35 11 3.3 6.9 5.4 6.7 C-1 16 6.6 11 6.4 C-2 4.4 2 3.4 2

FORMULATION EXAMPLE Formulation example 1

[0419] Granules are prepared using the following ingredients. Ingredients The compound represented by the formula (I) 10 mg Lactose 700 mg  Corn starch 274 mg  HPC-L 16 mg 1000 mg 

[0420] The compound represented by the formula (I) and lactose were made pass through a 60 mesh sieve. Corn starch was made pass through a 120 mesh sieve. They were mixed by a twin shell blender. An aqueous solution of HPC-L (low mucosity hydroxypropylcellulose) was added to the mixture and the resulting mixture was kneaded, granulated (by the extrusion with pore size 0.5 to 1 mm mesh), and dried. The dried granules thus obtained were sieved by a swing sieve (12/60 mesh) to yield the granules.

Formulation 2

[0421] Powders for filling capsules are prepared using the following ingredients. Ingredients The compound represented by the formula (I) 10 mg Lactose 79 mg Corn starch 10 mg Magnesium stearate  1 mg 100 mg 

[0422] The compound represented by the formula (I) and lactose were made pass through a 60 mesh sieve. Corn starch was made pass through a 120 mesh sieve. These ingredients and magnesium stearate were mixed by a twin shell blender. 100 mg of the 10-fold trituration was filled into a No. 5 hard gelatin capsule.

Formulation 3

[0423] Granules for filling capsules are prepared using the following ingredients. Ingredients The compound represented by the formula (I) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L  3 mg 150 mg 

[0424] The compound represented by the formula (I) and lactose were made pass through a 60 mesh sieve. Corn starch was made pass through a 120 mesh sieve. After mixing them, an aqueous solution of HPC-L was added to the mixture and the resulting mixture was kneaded, granulated, and dried. After the dried granules were lubricated, 150 mg of that were filled into a No. 4 hard gelatin capsule.

Formulation 4

[0425] Tablets are prepared using the following ingredients. Ingredients The compound represented by the formula (I) 10 mg Lactose 90 mg Microcrystal cellulose 30 mg CMC-Na 15 mg Magnesium stearate  5 mg 150 mg 

[0426] The compound represented by the formula (I), lactose, microcrystal cellulose, and CMC-Na (carboxymethylcellulose sodium salt) were made pass through a 60 mesh sieve and then mixed. The resulting mixture was mixed with magnesium stearate to obtain the mixed powder for the tablet formulation. The mixed powder was compressed to yield tablets of 150 mg.

INDUSTRIAL APPLICABILITY

[0427] The pyrimidine derivatives of the present invention have an inhibitory activity against a signal derived from Ras oncogene products, whereby they are effective for solid cancer having high frequency ras activation such as pancreatic cancer, colon cancer, and lung cancer. 

1. A compound represented by the formula (I):

wherein R¹, R², R³, and R⁴ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, an optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or R¹and R², R³ and R⁴, and R² and R³ each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered ring optionally containing O, N, or S, provided that R¹and R² and R³ and R⁴ do not form a ring when R² and R³ taken together form a ring; R⁵ and R⁶ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro; R^(B) and R^(C) are each independently hydrogen atom, alkyl, or alkyloxy; provided that in the case of both of R^(B) and R^(C) are hydrogen atom, R¹ is hydrogen atom or alkyl, R² is substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R³ and R⁴are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or R³ and R⁴ each taken together with the adjacent nitrogen atom form the same or different 3- to 7-membered ring optionally containing O, S, or N; X is —N(R⁷)—, —NH—NH—, —O—, or —S— wherein R⁷ is hydrogen atom or optionally substituted alkyl; Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl; Z is optionally substituted aryl or ptionally substituted heteroaryl; it optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
 2. A compound of claim 1, represented by the formula (II):

wherein R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, a non-aromatic heterocyclic group, acyl, substituted amino, alkyloxy, hydroxy, cyano, or nitro; R^(B) and R^(C) are each independently hydrogen atom, alkyl, or alkyloxy; provided that in the case of both of R^(B) and R^(C) are hydrogen atom, R⁸ is hydrogen atom or alkyl, R⁹ is substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R¹⁰ and R¹¹ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; W is —O—, —S—, or —N(R^(A))— wherein R^(A) is hydrogen atom or optionally substituted alkyl; R⁵, R⁶, X, and Z are as defined in claim 1; it optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
 3. A compound of claim 1, represented by the formula (III):

wherein R⁵, R⁶, and Z are as defined in claim 1, R⁸, R⁹, R¹⁰, R¹¹, R^(B) and R^(C) are as defined in claim 2, their optical active compounds, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates,
 4. A compound of claim 1, represented by the formula (IV):

wherein R⁸, R⁹, R¹⁰ and R¹¹ are as defined in claim 2; R¹² is hydrogen atom or alkyl; R^(D) and R^(E) are each independently hydrogen atom or alkyl; provided that in the case of both of R^(D) and R^(E) are hydrogen atom, R⁸ is hydrogen atom or alkyl, R⁹ is substituted amino, alkyloxy, hydroxy, cyano, or nitro; and R¹⁰ and R¹¹ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; V is optionally substituted aryl; it optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
 5. A compound of claim 1 represented by the formula (V):

wherein R⁵ and R⁶ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkyloxy, alkylthio, optionally substituted alkyloxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, halogen atoms, hydroxy, mercapto, optionally substituted amino, carboxy, cyano, or nitro; R^(F) and R^(G) are each independently hydrogen atom, alkyl, or alkyloxy; X is —N(R⁷)—, —NH—NH—, —O—, or —S— wherein R⁷ is hydrogen atom or optionally substituted alkyl; Y is optionally substituted 5-membered non-aromatic heterocycle-diyl or optionally substituted 5-membered heteroaryl-diyl; Z is optionally substituted aryl or optionally substituted heteroaryl; Q¹ is —NR¹R², —OR¹, or —SR¹, T¹ is —OR³ or —SR³ wherein R¹, R² and R³ are each independently hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; or R¹and R³, and R² and R³ each taken together with the adjacent heteroatom form 5- to 7-membered ring; it optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
 6. A compound of calim 5, represented by the formula (VI):

wherein Q² is —NR⁸R⁹, —OR⁸, or —SR⁸, T² is —OR¹⁰ or —SR¹⁰ wherein R⁸′, R⁹ and R¹⁰ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted non-aromatic heterocyclic group, acyl, optionally substituted amino, alkyloxy, hydroxy, cyano, or nitro; W is —O—, —S—, or —N(R^(A))— wherein R^(A) is hydrogen atom or optionally substituted alkyl; R¹, R⁶, R^(F), R^(G), X, and Z are as defined in claim 5; its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
 7. A compound of claim 5, represented by the formula (VII):

wherein R⁵, R⁶, R^(F), R^(G), and Z are as defined in claim 5; Q² and T² are as defined in claim 6; its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
 8. A compound of calim 5, represented by the formula (VIII):

wherein R² is hydrogen or alkyl; R^(H) and R^(J) are each independently hydrogen atom or alkyl; the other symbols are as defined in claim 6: its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate.
 9. A compound, its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate of claim 1 or 5, wherein R¹, R², R³, and R⁴ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl.
 10. A compound, its regioisomer, its optical active compound, its prodrug thereof, or their pharmaceutically acceptable salt, or their solvate of any one of claims 2 to 4 or claims 6 to 8, wherein R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen atom, optionally substituted alkyl, alkenyl, alkynyl, or acyl.
 11. A pharmaceutical composition which contains as active ingredient a compound as described in any one of claims 1 to
 10. 12. A pharmaceutical composition for use as an antitumor agent which contains as active ingredient a compound as described in any one of claims 1 to
 10. 13. A pharmaceutical composition for use as a cytostatic agent which contains as active ingredient a compound as described in any one of claims 1 to
 10. 14. A pharmaceutical composition for use as an inhibitor against a signal derived from Ras oncogene products which contains as active ingredient a compound as described in any one of claims 1 to
 10. 15. Use of a compound of any one of claims 1 to 10 for the preparation of a pharmaceutical composition for treating cancer.
 16. A method of treating a mammal, including a human, to alleviate a pathological effect of cancer, which comprises administration to the mammal of a compound as described in any one of claims 1 to
 10. 